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M2M Unit 3 > Week 1 > Flashcards

Week 1 Flashcards

1
Q

Benign Tumor

A

made up of non-invasive OR metastatic cells, but have lost many growth factors and specialized function of normal cells.
They are immortal

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2
Q

Mutational signatures

A

because cancers harbor many somatic point mutations, some cancers have mutational signatures consistent with a certain carcinogenic agent.
ie. UV light and melanoma and tobacco and lung cancer

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3
Q

Cytogenetic Analysis

A

used to study cancer to detect major genetic abnormalities in cancer cells and are used in clinical diagnosis
can detect: translocation and gene deletions, Loss of Heterozygosity, anueploidy.

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4
Q

Anueploidy and prognosis

A

poor prognosis

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5
Q

Autosomal Dominant Cancers

A

Familial Adenomatous Polyposis
Familial Retinoblastoma
Breast and Ovarian Cancer
Wilms Tumor

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6
Q

Autosomal Recessive Cancers

A

Xeroderma Pigmentosa
Ataxia Telangiectasia
Blooms Syndrom
Fanconi’s Congenital aplastic anmeia

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7
Q

Retinoblastoma Gene/protein

A

Tumor Suppressor
Ch 13a14 mutation
deletion, partial deletion, or rearrangement (due to PCR and southern blot)

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8
Q

Retinoblastoma Prevalence

A

Rare, pediatric disorder 1/20,000 infants

Autosomal Dominant

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9
Q

Inherited Retinoblastoma

A

DNA from normal tissue, or unaffected family, shows a defect in one RB gene, but one normal copy. They are Heterozygous, but they acquire homozygosity for the RB gene.

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10
Q

Retinoblastoma - how does Loss of heterozygosity occur

A

1) local events
2) somatic recombination (most common)
3) loss and duplication
4) chromosome loss

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11
Q

Growth in normal cells

A

Growth factors (ras, Jun) and EGFR activate CDK4,6; cycD1-3, CDK2, and CycE.
CDKS are always present, but only activated by CycD or cycE.
When CDK are activated they phosphorylated RB to inactivate it to promote cell proliferation.

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12
Q

RB hyperphosphorylation

A

Occurs in rapidly proliferating cells at S or G2

Cells begin to divide

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13
Q

RB hypophosphorylation

A

in non-proliferating cells in G0 or G1 of cell cycle.

Repressed entry into S phase

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14
Q

CDK phosphorylates RB

A

to inactivate RB to allow the cell to proceed from G1 to S

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15
Q

HPV E7

A

Binds to RB protein to inactivate it and promote cell proliferation in cervical cancer

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16
Q

Sporadic cases of RB

A

very rare 1/10^8

characterized by unilateral retinoblastoma or single tumor

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17
Q

Inherited cases of RB

A

Inherit one RB mutation and obtain second mutation

Characteristic of bilateral retinoblastoma or multiple tumors in the same eye

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18
Q

What types of cancer does RB predispose you to?

A

1) small cell lung tumors

2) breast cancer

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19
Q

p107 and p130

A

homologs to RB in human cells. They are not located in the retina, but the are located in the pituitary, so they provide protective role in tumor development in pituitary

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20
Q

APC

A

tumor supressor gene in Familial Adenomatous Polyposis

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21
Q

FAP

A

1/10,000
Autosomal Dominant disorder
but increased chance of LOH (90% will develop colon cancer by 50)

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22
Q

adenomatous polyps

A

characteristic of FAP

develop during the first 20 years of life, but become malignant by LOH

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23
Q

APC Gene

A

mapped on Ch 5q

encodes a cytoplasmic protein that regulates the localization of Beta-Catenin

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24
Q

Beta-Catenin

A

is normally sequestered to plasma membrane by Ecadherin

when WNT binds to Frizzled, it is released by membrane and can go to the nucleus to act like a transcription factor

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25
Q

APC Protein

A

cases the degradation of free beta-Catenin in cytoplasm

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26
Q

Mutated APC

A

Beta-Catenin cannot be degraded in the cytoplasm, so it moves to the nucleus t activate TCF/Lef and promotes the transcription of oncogenes like c-myc
Thus loss of APC causes over epxression of the c-myc oncogene to result in polyp formation and metastasis

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27
Q

BRCA1 and BRCA2 Mutations

A

Inherited mutations 5%
and inherited cases display LOH
Extremely penetrant

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28
Q

Acquired breast cancer

A

somatic mutations of BRCA1 or 2 have not been found in tumors, mutations in other genes may affect BRCA1 and BRCA2 function indirectly.

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29
Q

BRCA1 and BRCA2

A

are regulating checkpoint proteins that function in DNA repair

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30
Q

Fanconi’s Anemia D1 Gene

A

BRCA2 homozygous mutation that develops at 5 years of age.
They can get a bone marrow transplant and anemia is cured.
But they are at increased risk of leukemia head and neck cancer, ano-genital cancer, NOT high risk of breast cancer.

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31
Q

Why don’t Fanconi’s Anemia get breast cancer?

A

every cell in their body lacks BRCA2 gene

Women who only get breast cancer occur by loss of WT allele.

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32
Q

p53 mutations

A

mutation found in 50% of cancers
All through somatic events, rarely inherited
Most are due to missense mutations (75%)

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33
Q

p53 gene

A

tumor supressor gene
mutations in this gene causes the accumulation of mutations at a much higher rate
“guardian of the genome”
tetramer, mutant p53 binds to WT p53 to inactivate it - making it a “dominant negative”

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34
Q

Properties of p53

A

1) transcription factor to express gene that prevent replicating foreign or damaged DNA
2) apoptosis

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35
Q

HPV E6

A

inactivates p53 by leading to its degradation

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36
Q

HPV

A

normally integrates into DNA and destroys E1 repressor and promotes E6 and E7 to inhibit both RB and p53
When you put back in the E1 gene, the cells stop growing and proliferating.
If you step really hard on the tumor suppressors, it doesn’t matter how hard you press on the oncogenes!

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37
Q

retroviruses

A

RNA, membrane enclosed viruses that bud from the cell membrane and do not kill infected cell.

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38
Q

What genes promote the replication of a virus

A

Gag, Env, Pol.

replicates through intermediate proviral DNA and integrates into the host cell genome.

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39
Q

what gene in viruses in cancerous

A

v-onc has the ability to rapidly transformed appropriate cells into a malignant phenotype.

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40
Q

pp60c-src

A

a protein coded by v-src gene that is a membrane bound protein kinase that phosphorylates tyrosine residues, affecting gene expression

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41
Q

v-erb-B

A

codes for a protein that is similar in structure to EDFR.
It exhibits tyrosine specific protein kinase activity, so it is constantly sending signals inside cell to proliferate without growth factor binding.

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42
Q

v-ab;

A

similar to the c-ABL that is a protein kinase that phosphorylated tyrosine residue.

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43
Q

Products of oncogenes resemble

A

mimic hormones or growth stimulating factors either by resembling natural hormones or affect structure of the cell surface receptors.

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44
Q

Proto-Oncogenes

A

c-onc genes
cellular prototypes of v-onc in eukaryotic cells
involved in spontaneous malignancies that have nothing to do with a retrovirus.
Can produce quantitative changes (too much protein) or qualitative changes (overactive or unregulated protein)

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45
Q

Properties of c-onc

A

1) most are quite different from the v-onc genes

2) if v-onc gene originated from c-onc, these arrangements occurred during or after capture

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46
Q

Human Bladder Cancer Cells

A

have a point mutation in codon 12 or 16 of c-ras and produce protein is that is always on

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47
Q

Amplification of c-onc

A

N-myc is found amplified in neuroblastoma.
HER2/neu encodes for integral membrane protein kinase that is amplified in 20% of breast cancers
Higher levels correlate with poor prognosis

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48
Q

Translocations of c-onc

A

also an indication of poor prognosis

inappropriate and high level expression of BCR-ABL

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49
Q

Cancer “targeted” therapy

A

tumor cells can be reversed by blocking the actions of oncogenes or by added missing tumor suppressors.

1) at gene level
2) or with drugs or antibodies

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50
Q

Herceptin

A

antibody drug that inhibits the erbB2 protein and extends the life of breast cancer patients by increasing the efficacy of radiation.

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51
Q

Heat map

A

is created by hybridization of the tumor DNA to a gene chip containing human genomic DNA sequences.
Red indicates increases and blue/green indicates decreases.
Used to correlate many types of molecular data (CNV, gene expression, mutations) with relevant clinical info (tumor grade, survival, age, tumor state).

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52
Q

LFS

A

Li-Fraumeni Syndrome is a rare inherited genetic cancer disorder that greatly increases one’s risk of developing cancer during their lifetime. Sometimes people with LFS develop multiple cancers and multiple tumors often in childhood or as young adults.
70% associated with mutation in p53

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53
Q

LFL

A

Li fraumeni like syndrome

only 40% are associated with p53 mutations

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54
Q

clinical benefits of identifying molecular basis of LFS?

A

1) identification of mutation provides diagnostic certainty
2) avoid delay in diagnosis of second tumor
3) avoid radiation
4) prenatal diagnosis may be offered to families

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55
Q

Diagnostic criteria of LFS

A

proband with sarcoma diagnosed before 45 AND First degree relative with any cancer under 45 and
first or second degree relative with any cancer under 45 or a sarcoma at any age

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56
Q

Diagnostic criterial of LFL

A

A proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age AND
A first- or second-degreerelative with a typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age AND
A first- or second-degreerelative with any cancer under the age of 60 years.

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57
Q

how is LFS or LFL detected?

A

Next Generation sequencing

Used to sequence only the Hot Spots of exons 5-9, or full length mRNA then check hCHk2 or PTEN

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58
Q

Two hit model of LFS

A

Hit 1: mutation on p53 in codon 273 (CGT –> CAT; arg to his)
Hit 2A: amplification of HER2 to cause breast cancer
Hit 2B: EGFR mutation in exon 21 to cause lung cancer

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59
Q

How do “hits” occur in cancer?

A

1) point mutations in oncogenes or tumor suppressors
2) amplifications and deletions
3) epigenetic silencing by methylation
4) insertion of retrovirus containing an oncogene

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60
Q

function of normal p53 gene

A

Protection from carcinogens
a transcription factor, regulation of mRNA, target of conventional chemotherapy and drugs are available to activate p53 without DNA damage.

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61
Q

what does p53 recognize?

A

stress signals from gamma irradiation, UV, genotoxic drugs, nutrition deprivation, heat/cold shock

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62
Q

how do genotoxic drugs activate p53?

A

they stimulate ATM and ART to activate Chk1 and Chk2

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63
Q

how is p53 regulated?

A

It is not in high concentration at all times, only induced when needed.
MDM2 and MDMX bind to p53 and inbits it

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64
Q

What does p53 cause?

A

cell cycle arrest; apoptosis; inhibition of angiogenesis and metastesis; DNA repair and damage prevention; inhibition of mTOR pathway; exosome mediated secretion; p53 negative feedback; cellular senescence.

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65
Q

p53 domains

A

Transcription activation domain; unstructured spacer region, tetramerization domain, NES, C-terminal DNA binding regulatory element
Mutation in LFS most often occur in DNA binding domain

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66
Q

how does p53 regulate growth arrest?

A

Activates P21, GADD45, 14-3-3omega to inhibit CDK1 (inhibits from going into S phase) and CDC2 (M phase)

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67
Q

how does p53 regulate apoptosis?

A

activates Bax and Apaf1 which activate CytoC

Cycto C and Apaf1 bind to caspase9 to lead to apoptosis

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68
Q

Von hippel Lindaue

A 
AD
1:36,000
high penetrance by 65; >95%
high variability of disease severity
20% due to de novo mutations
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69
Q

VHL gene

A

ch 3p25-26
Tumor Supressor Gene
Part of protein complex that targets unwanted proteins for proteosomal degradation by ubiquitination

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70
Q

VHL protein actions

A

1) regulation of hypoxia inducible TF
2) suppression of aneuploidy
3) maintenance of primary cilia/stabilization of microtubules.

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71
Q

VHL loss or accumulation

A

leads to HIF accumulation, high rate of aneuploidy, disruption of primary cilia to lead to renal cysts and renal cell carcinoma

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72
Q

VHL and HIF normoxic

A

HIF is hydroxylated by proline and asparagine hydroxylase

in presence of normal VHL, HIF is ubiquitinated by VHL protein and undergoes proteosomal degradation.

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73
Q

VHL and HIF hypoxic condition

A

mutated VHL behave like under hypoxic conditions.
HIF does not get hydroxylated and HIF is not degraded.
HIF accumulates and goes to nucleus to activate transcription factors that promote cancer growth and survival in low O2 conditions.

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74
Q

What types of genes get expressed with HIF?

A

gene involved in angiogenesis, metabolism, apoptosis to act on surrounding vasculature to make new blood vessels to provide cancer with nutrients and oxygen for survival.

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75
Q

What is the major cause of death in patients with VHL?

A

metastatic renal cell carcinomas

CNS hemangioblastomas

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76
Q

Hemangioblastoma

A

a tumor that originates from the vascular system - blood vessel rich tumors.

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77
Q

Cerebellar and Spinal Cord Hemangioblastomas - VHL

A

Occur in 60-80% of patients
Mean age of diagnosis in 30 years
located in cerebrum, brainstem, cervical spine, but NOT forebrain

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78
Q

Retinal Hemangioblastoma - VHL

A

occurs in 50% of patient
mean age at diagnosis is 25 years
if untreated lesions lead to blindness

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79
Q

Bilateral kidney cysts and clear cell renal carcinomas - VHL

A 
Renal cortical tumors characterized by malignant epithelial cells
occur in 75% of patients by age of 60
mean age of 39
accounts for 50% of deaths
can be cystic or solid tumors
tend to be bilateral and multiple
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80
Q

Pheochromocytomas - VHL

A

hormone secreting tumor that occurs in adrenal glands, but can develop tissues outside adrenal gland around arota, head and neck
25% of patients
mean age of diagnosis is 27

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81
Q

Type I VHL

A

hemangioblastoma + clear cell renal carcinoma
due to partial or total loss of VHL –> improper folding.
Molecular defect: upregulation of HIF
low risk of phenocyhromocytoma

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82
Q

Type 2 VHL

A

pheochromocytoma +/- hemangioblatoma +/- Clear cell renal carcinoma

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83
Q

Type 2A VHL

A

Hemangioblastoma + pheochromocytoma
VHL missense mutation
Molecular defect: up regulation of HIF, inability to stabalize microtubules
low risk of RCC

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84
Q

Type 2B VHL

A

Hemangioblastoma + pheochromocytoma + clear cell regnal carcinoma
VHL missense mutation
up regulation of HIF

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85
Q

Type 2C VHL

A 
pheochromocytoma only
VHL missence
pVHL maintains ability to down-regulate HIF
decreased binding to fibronectin
defect in fibronectin matrix assembly.
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86
Q

Clear Cell Renal Carcinoma

A

3/4 of kidney cancers
only 4% inherited
must most are due to VHL loss or mutation
patients at risk of developing 600 tumors per kidney

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87
Q

Treatment of ccRC

A

surgical resection with either partial or radical nephrectomy.
therapy including: vascular endothelial growth factor receptor, tyrosine kinase, mTOR inhibition, immunotherapies.

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88
Q

Intracellular Fluid Volume

A

2/3
27 L
mitochondrial, vesicular, nuclear, sub-compartmental

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89
Q

ICF contents

A 
14 mM Na
145 mM K (permeabe)
5 mM Cl- (permeable)
126 mM Proteins
55,000 mM water (permeable)
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90
Q

Extracellular Fluid Volume

A

interstitial vluid, lymph, plasma

1/3 or 13L

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91
Q

ECF contents

A 
140 mM Na
5 mM K (+)
140 mM Cl (+)
0 Porteins
55,000 mM water (permeable)
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92
Q

Ion Channel structure

A

central pre with four peptide helices arranged symmetrically.

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93
Q

Reflection coefficient

A

how easily a permeating solute will cross the membrane

0 is as easily as water; 1 is not at all

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94
Q

electrochemical gradient

A

movement of ions due to :

1) concentration difference
2) membrane potential or electrical potential difference.

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95
Q

Nernst equation

A

used to determine when the membrane potential equilibrium will be reached
= 60/z * log (Co/Ci)

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96
Q

What does it mean when Vm = E

A

while concentrations are different, the internal charge is sufficient to keep ions from diffusion with concentration gradient.

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97
Q

V=IR what does these mean?

A

V = driving force = Vm-E

R use 1/R = Permeability or G - number of channels open

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98
Q

Hyponitremia

A

fall in external Na concentration
Ek stays the same
moves the ENa towards zero.
causes Vm to hyperpolarize slightly.

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99
Q

Hyperkalemia

A

rise in external potassium

Ek gets much ore positive and we see a very large depolarization.

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100
Q

Sign of hyperkalemia

A

severe infection, weight loss, hypotrophy, water loss and loss of K.
acute hemolytic anemia
due to crush injury, electrocution.

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101
Q

Glucose Transport

A

Glucose transports in either direction
glucose is trapped in the cell because it gets phosphorylated into G6P that does’t fit into the glucose transporter.
Glucose uptake is regulated by insulin

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102
Q

calcium pump in heart

A

at rest: ventricles are filling with blood and heart pumps 1 calcium out with the inward transport of 3 Na.’
During beat: calcium pumps into the cell in exchange for 1 Na and 1 K..

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103
Q

Digitalis

A

drug that blocks the Na/K pump
allows intracellular Na to increase, reducing secondary active transport of Na/Ca
allows Ca to rise and increase cardiac contractility.

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104
Q

H/K transporter

A

Infusion of K causes acidemia

Infusing H causes hyperkalemia

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105
Q

Absorption of salt at BL membrane

A

low sodium permeability and HIgh K permeability

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106
Q

Absorption of salt at AP membrane

A

highly permeable to Na and low permeability to K

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107
Q

Absorption of Na across epithelium

A

Na leads into the cell passively across the apical membrane and down electrochemcial gradient.
Pumped out of cell by Na/K pump on BL side.
results in a positive charge, causing Cl to pass freely with electric force and drags water along.

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108
Q

Mechanism of cholera

A

Acetyl Choline from parasympathetic NS binds to receptor in epithelium and causes the release of Ca into the cytoplasm. This stimulates adenylyl cylase that uses ATP to make cyclicAMP. cAMP activates Cl- channel on apical membrane to release serous fluid. Choleral activates adenylyl cylase to cause more release of serous fluid.

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109
Q

Refractory periods

A

absolute : no stimulus, no matter how strong, can evoke an AP
relative refractory: stronger than normal may evoke AP

This id due to Na inactivation gates being close in some channels and the cell needs time to reopen all inactivation gate.
also due to time it takes to close K channels.

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110
Q

Hyperkalemia and action potentials

A

gives steady depolarization from rest.

it allows some inactivation gates to close, so when a stimuli comes along it make not lead to an AP

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111
Q

Adding local anesthetic to axon for action potential

A

local anesthetic blocks sodium channel

Depolarization spreads, but it gradually decreases and is unable to reach threshold.

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112
Q

Small diameter axons and action potentials

A 
conduct at lower velocity
harder to stimulate
low safety factor
blocked easily by anesthetic
no myelin
pain fibers have small diameters
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113
Q

Large axons and action potentials

A 
conduct at higher velocity
easy to stimulate
high safety factor
myelin sheath
motor axons have larger diameters
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114
Q

Hyperkalemia and action potential

A

extracellular K depolarizes cell and disrupts rhythm of SA node.
normally SA node undergoes spontaneous depolarization to reach threshold to fire AP.
hyperkalemia depolarization SA node and causes arrhythmias
Calcium can bind to the fixed negative charges outside the cell surface and tricks Na channels into thinking membrane is hyperpolarization and raises the threshold of AP.

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115
Q

Carbohydrates on membrane proteins are important for…

A

1) development
2) immune response
3) binding of viruses and toxins
4) proper protein folding

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116
Q

Three classes of amphipathic lipids

A

1) phospholipids
2) spingolipids
3) cholesterol
all derived from glycerol except for spingolipids

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117
Q

structure of plasma membrane

A

negative lipids on the inside: Phosphadidylserine, phsophatidylthanolamine, phosphatdiylinostilol
positive on outside: spingomeyline, glycolipids
cholesterol is equally distributed.

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118
Q

structure of ion channels

A

Four membrane spanning domains
six alpha helices (S1-S6)
Na and Ca have four domains linked by polypeptides
K each domain in a separate peptide
S4 has positive residues (lys or arg) every 3rd position - voltage sensing
S5, S6 and P loop is the ion conducting pathway

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119
Q

What form the voltage sensing region of an ion channel

A

S4 - lys and arg every 3rd position

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120
Q

metabotropic receptors

A

A metabotropic receptor is a type of membrane receptor of eukaryotic cells that acts through a secondary messenger. It may be located at the surface of the cell or in vesicles.
G protein coupled

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121
Q

Ionotropic Receptor

A

Ionotropic receptors form an ion channel pore.

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122
Q

Pentameric Ligand Gated Chennel

A

Cys-Loop family
GABA, nACHR, Serotonin (5-HT3Rs)
heteropentamers (5 subunits)
each subunit has four transmembrane alpha helices (m1-M4) with M2 assembling around channel.

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123
Q

Tetrameric ligand gated channels

A

Ionotropic glutamate receptors
NMDA - through to be involved in associative learning
4 subunits, each with 3 alpha helices
2 of the 4 subunits bind to glutamate and the other two bind to glycine.

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124
Q

Chloride Channels

A

CLC family - establishing negative membrane potential
Dimers in which each subunit has an ion permeation pathway with gate for chloride
each pathway is independent of each other.
another gate controls the pathways simultaneously.
mutation leads to myotonia

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125
Q

Aquaporin Channel

A

tetramer
each subunit contains permeation pathway for water, no entry of ions (especially protons).
Central pore allows ion permeation.
expressed in tissues with rapid water movement.

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126
Q

percentage of cytopslam

A

54%

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127
Q

Mitochondria percentage

A

22%

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128
Q

Rough ER percentage

A

9%

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129
Q

percentage of Ser and Golgi

A

9%

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130
Q

percentage of nucleus

A

6%

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131
Q

Protein transmembrane domain I

A

single TMD and amino acid in ER lumen.

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132
Q

Type 2 domain of transmembrane proteins

A

Single TRM and amino terminal in cyto
ER ss doens’t have to be N-Terminus
positive amino acids ortient amino end to cytosol.

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133
Q

Type 3 domain of transmembrane proteins

A

similar to Type II1 proteins except positive charge residues on C terminal side of signal ancho.

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134
Q

N-linked glycosylation

A

carbohydrate complex added to asparigine in ER lumen
must be Asn - X - Ser/Thr
catalyzed by oligosacchardie

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135
Q

Dolichol

A

lipid carrier that holds sugars

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136
Q

how do statins work?

A

inhibit HMG-CoA reductase is important in dolichol sugar complex.

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137
Q

pH differences between golgi and ER

A

ER is neutral

Cis-Golig 6.7

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138
Q

Function of Golgi

A

synthesis of complex spingolipids from ceramide
post translation modification of proteins and lipids - glycosylation and sulfation
Proteolytic processing
sorting of proteins and lipids for post-golgi compartments

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139
Q

Hereditary spastic paraplegia

A

a disease that has many different mutations that cause the same disease
progressive stiffness and contraction of lower limbs
mostly due to mutations in membrane trafficking

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140
Q

Phagocytosis

A

carried out by macrophages or neutrophils

recognize foreign organisms or apoptotic cells, engulf them and deliver to lysosome.

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141
Q

pinocytosis

A

specific uptake of ligands and receptor

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142
Q

LDL Receptors and cholesterol degradation

A

cycles between plasma membrane and lysosome
clustered in membrane pits due to AP2 (adaptor protein complex 2) that binds to clathrin.
after clathrin disassembles, forms early endosome.
Fuses with late endosome, where acidic pH causes degradation of LDL into cholesterol, fatty acids, and amino acids that are transported to cytoplasm for recycle.

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143
Q

Caveolae

A

140-150 small endocytic vesicles that form without protein coats
Important in lipid rafts
Caveolin is the scaffolding protein that coordinates the protein complex in these vesicles.

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144
Q

HSP 70

A

binds to hydorphobic patches on incomplete folded proteins and prevents aggregation

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145
Q

HSP 60

A

forms large barrel shape to make isolated chamber
ATP dependent
GroES is the cap

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146
Q

N-glycanase

A

marks misfolded protein that exits the ER for utiquitation

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147
Q

E1

A

ligase that binds and activates ubiquitin (activation)

only one!

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148
Q

E2

A

ligase that is involved in conjugation

we have 50 of these

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149
Q

E3

A

ligase that facilitates transfer from E2 to lysine of protein
then attaches string of more ubiquitins to form polyubiquitin chain
(ligation)
500 different E3

150
Q

Immunoproteosome

A

interferon gets up regulated and forms new proteosomes with specialized cleavage that degrades viral peptides, where they are transfered to the ER and transported to a the surface of cell to prevent future infection by recognition by T cells

151
Q

Tay Sachs

A

defects in beta-hexamidisade

breaks gangliosides in neurons

152
Q

Gaucher’s disease

A

beta-glucosidase breaks down glucoceramide in monocytes and leukocytes

153
Q

Niemann-Picks

A

Phingomeylinase breaks down phingomyelin in macrophages

cholesterol transporter transports cholesterol from lysosome to cytosol

154
Q

microautophagy

A

direct invagination of the lysosomal membrane

155
Q

Chaperone mediated autophagy

A

delivers specific proteins to lysosomes
sequence with KFERQ is recognized by heat shock protein HSC70 which interacts through a series of proteins with LAMP-2A in lysosome.
This causes the proteins to insert into lysosome for degradation

156
Q

Macroautophagy

A

complicated signaling that leads to creation of double membrane vesicle that encapsulates a bunch of to be degraded material that fuses with lysosome for hydroxylase degradation.

157
Q

When is macroautophagy used?

A

for longer lived proteins, degradation of organelles.

158
Q

regulation in macroautophagy

A

some of it is very specifically regulated, but sometimes it also grabs everything in the area as well.

159
Q

amphisome

A

fusion of autophagosome with endosome, eventually fuses with lysosome

160
Q

autophagolysosome

A

autophagosome fuses directing with lysosome

161
Q

Functions of macroautophagy

A

1) recycle proteins and molecueles
2) remove organelles
3) allow survival during stress
4) neuro-protection (remove protein aggregates)
5) remove intracellular pathogens
6) aging

162
Q

starvation and autophagy

A

increases

163
Q

over-eating and autophagy

A

decreases

164
Q

atg genes

A

regulate autophagy; more than 20 genes associated with formation of autophagosomes

165
Q

Autophagic process

A

1) induction
2) Vesicle nucleation: phagophore
3) Vesicle expansion: omegasome
4) cargo targeting - either random or specrific
5) vesicle closure
6) vesicle fusion with endosome: amphisome
7) vesicle fusion with lysosome: autolysosome

166
Q

cargo targeting proteins in autophagy

A

LC3 recognizes ubiquitinated proteins

p62 recognizes and binds to the LC3

167
Q

Beclin-1

A

when cleaved by caspases, switches autophagy off and leads to more effective apoptosis

168
Q

Regulation of Beclin-1

A

When the BH3 domain interacts with BCL2 and BCL-XL, no autophagy can occur and apoptosis is promoted.
when BH3 is in abundance and interacts with BCL2 and BCL-XL, it is released by beclin1 and autophagy is promoted.

169
Q

Cancer drugs and Beclin-1

A

cancer drugs inhibit BH3 interaction with BCL2/BCL-XL to induce apoptosis

170
Q

Rapamycin

A

mTOR inhibitor

activate autophagy and decrease apoptosis

171
Q

indience of DKA in US

A

increasing 3-5% each year

172
Q

basic identification of DKA

A

ill appearance, rapid breathing, nausea/vomiting, belly bain, dehydration, hyperglycemia, ketones in urine/blood, acidosis

173
Q

hyperglycemia - DKA

A

> 200 mg/dl
A1C greater or equal to 6.5
fasting plasma glucose above 126

174
Q

Acidosis - DKA

A

due to beta oxidation of fatty acids to generate hydrogen and ketone bodies
body compensates by breathing deeply and at faster rate

175
Q

aldosterone

A

hormone that stimulates the retention of sodium at the expense of potassium in the urine
during dehydration, to give body depletion of potassium.

176
Q

how does acidosis occur in DKA

A

there is an influx of hydrogen into cell and efflux of postassium, gives appearance of hyperkalemia despite postassium depletion.

177
Q

Hematochezia or Blood in Stool for Crohn’s vs ulcerative colitis

A

Rarely seen in crohn’s and common in UC

178
Q

Inflammation in Crohn’s Vs. UC

A

C; Transmural

UC: mucosal

179
Q

OPS group

A

o-specific polysaccharide

identifies different strains of cholera

180
Q

Pili

A

subports colonization of cholera by binding to epithelial cells

181
Q

Toxin

A

A;5B

Beta binds to epthitelial surface and brings A along side.

182
Q

Receptor of Cholera toxin

A

galglioside GM1

183
Q

Mechanism of Cholera

A

Cholera beta subunit binds to epitheliu and gets endocytosed
G protein is activated and activates adenylate cylase to make cAMP
cAMP binds to CFTR receptor to cause release of intracellular Cl and water and Na follow through gap junctions.

184
Q

Pathogenesis of Cholera

A

1) innoculum by oral ingestion or infestation
2) pH - passage of toxin through gastric acid barrier
3) flagella - allow for penetrance of mucus layer to SI
4) TCP - adherance to the brush border of intestinal epithelium
5) manipulation which gives rise to symptoms

185
Q

EBV infections in MS

A

it occurs early in life in tropics, but it is most detrimental later in life in higher socioeconomic countries.

186
Q

First-demyelinating event in MS

A

deficit loss in vision, weakness, balance.
If you stop the immune response and repair damage, can lead to complete recovery.
also known as Clinically Isolating Syndrome

187
Q

Relapsing Remitting in MS

A

frequent inflammation, demyelination, axonal transection
8/10 MS patients are in the stage
recovery becomes less and less perfect and leads to progressive degeneration

188
Q

Common problems with MS

A

sensory loss, vision loss, poor balance and motor, cognitive problems, pain, urinary problems, sexual problems, fatigue

189
Q

TH1 vs TH2

A

TH1 is proinflammaotry cytokine that promotes lesions

TH2 is antinflammatory

190
Q

immunopathogenesis of MS

A

T cells activate macrophages to exchange phagocytic activity, produce cytokines, release toxic mediates (NO) to promote myelin loss and axonal loss.

191
Q

clostridium botulinum toxin

A

cleaves SNARE proteins to prevent NT fusion in neuromuscular junction

192
Q

Syntaxin

A

t-snare
present at Plasma membrane
Transmembrane domain with 1 coiled domain and 3 H domains

193
Q

SNAP-25

A

present in Plasma membrane

two coiled domain and palmytilation CCC which anchors in the PM

194
Q

VAMP

A

snare protein on the vesicle

transmembrane domain and one coiled region

195
Q

NSF

A

ATPase
uses ATP to take SNARE complexes and unwind them after vesicle fusion
forms hexamer and each unit requires ATP

196
Q

alpha-SNAP

A

bings to SNARE complex after fusion and recruits NSF

adaptor protein to NSF

197
Q

n-sec1

A

chaperone protein that helps syntaxin protein fold correctly

But stays bound to syntaxin and block it until vesicle fusion is needed

198
Q

n-sec1 regulation

A

Syntaxin has 3 H domains that forms an alpha helix coild coil with itself and its own coil domain to prevent fusion.
nsec1 binds to stabilize it until calcium is release and NT released.

199
Q

Viral envelope

A

full of clusters of fusogenic proteins that play a role with fusion with the host

200
Q

gp41

A

HIV fusion proteins with a transmembrane domain and two H domains

201
Q

fusogentic peptide

A

coiled coil with two alpha helices in antiparallel to bring transmembrane domain and fusogenic peptide together.
folded within the virus wall because it is hydrophobic, but host cell triggers conformational change to assume a metastable intermediate that inserts itself into host and causes a hemifusion

202
Q

Influenze virus vesicle fusion

A

stable and metastable conformational change occurs with changes in pH

203
Q

HIV virus vesicle fusion

A

gp120 sits on top of gr41 to inactivate it.
When binds to CD4 receptor, gp120 is released and gp41 forms metastable conformation and fuses.
Most anti-HIV drugs target coiled coil to prevent formation so it can’t fuse.

204
Q

p53 mutations

A

leads to is mislocalization from nucleus to cytoplasm to allow DNA damage to replicate

205
Q

NFkB

A

mislocalized to the nucleus from the cyto for anti-apoptotic factors to be transcribed

206
Q

Facilitated transport of hydrophilic molecules through nuclear pore

A

amphiphilic receptor (carrier) forms complex with hydrophilic molecule (cargo)
The cargo has either the NLS or NES
the carrier are in the inside pore and the cargo is on the periphery
Requires energy to break apart cargo and carrier
can go against concentration gradient.

207
Q

Nuclear Localization Signal

A

basic residues of arginine

208
Q

Nuclear Export Signal

A

Leucine Rich

209
Q

Receptor Family Cargo Transporters

A

Beta-Karyopherin

interacts directly with FG nups and cargo

210
Q

Adaptor Cargo Transporters

A

Alpha-Karyopherin
has binding site to specific cargo and receptor to facilitate transport.
cant be transported by itself

211
Q

NTF2

A

transports Ran GTP

212
Q

NXF1/NXT1

A

transports mRNA and rRNA

213
Q

RanGTP

A

facilitates breaking up carrier and cargo in nucleus, remains attached to transporter and is exported. RanGTP is hydrolyzed to free transporter.

214
Q

NTF2

A

dedicated to recycling RanGDP from cyto back itno nucleus to be repeated.
Single protein carries two ranGDP into nucleus

215
Q

Cysplasmic levels of RanGTP vs RanGDP

A

low ranGTP and high RanGDP

216
Q

Nucleus levels of RanGTP and RanGDP

A

high levels of RanGTP and low RanGDP

217
Q

RCC1

A

anchored into the chromatin that tethers it to the nucleus

Exchanges GDP to GTP to re-establish RanGTP

218
Q

RanGTP vs RanGDP

A

the extra phosphate exposes loop that interacts with proteins in the nuclear pore to facilitate export

219
Q

Ran BP1

A

relieves the block in the cytoplasm and allows RanGTP to be hydrolyzed.

220
Q

Importin Alpha

A

also karyopherin alpha

more than 7 family members in man

221
Q

Importin Beta

A

more than 20 family members
karyopherin Beta
doesn’t require adaptor protein

222
Q

how is mRNA exported?

A

NXF1 and NXT1
binds when remodeling of RNA has occurred at the nuclear basket.
Remodeling also occurs at the cytoplasmic space in an energy dependent (ATP) fashion to allow cytoplasmic Rnbp to facilitate exit from pore.
Much slower than protein tranpsort

223
Q

how is nuclear export regulated?

A

Gene expression, composition of nuclear pore complex, availability of carriers, cargo, sequestration, masking of signals

224
Q

how does the cargo regulate nuclear transport?

A

conformational change to expose NES/NLS

covalent modifications that potentiates binding site - phospho, methyl, ub, polyation

225
Q

how does sequestration regulate nuclear transport?

A

binding partners in nucleus or chromatin or cytoplasm/cytoskeleton which sequesters TF until signal is transduced

226
Q

BRCA2 mislocalization

A

mutation disrupts interaction with binding partner to allow it to be exported with RAD51 to cause metastatic cancer

227
Q

p53 mutation - nuclear transport

A

karyoferins are upregulated

p53 is aberrantly transported out of nucleus due to large amounts of CRM1 to change balance of import and export.

228
Q

selective inhibitors of nuclear export

A

bind to CRN1 to inhibit export, can restore normal health with p53 mutation

229
Q

Microtubule Structures

A

25 nm
Continuous cylinders, 13 protofilaments, alternating alpha tubulin and beta tubulin
Bound to GTP or GDP
polar: munis end is alpha, plus end is beta

230
Q

microtubule dynamics

A

GTP cap stabalizes
MT severing proteins - promote depolymerization
MT Binding Proteins stimulate GTP hydrolysis

231
Q

MT severing proteins

A

ATPase hexamer
Katanin
spastin - hereditary pastic paraplesia
figetin

232
Q

Function of Microtubules

A

Cellular cytoskeleton
intracellular transport
cell division
cilia

233
Q

Intracellular transport

A

Microtubules
Kinesin goes to + end in periphery (ATPase trigers power stroke)
Dynein: goes to - end in cell body

234
Q

Kinesin

A

dimer with head domain: binds to MT and ATP; N terminus

Tail domain: C-terminus, binds to cargo with adapators

235
Q

Cargo of Microtubules

A

RNA, vesicles, microtubules

236
Q

why is dynein important?

A

transport back to cell body of NGF to maintain stable neuron connection.

237
Q

Microtubules in Cell division

A

Astro-MT contact PM
Kinetochore MT: attach to sister chromatids
Central spindle MT: attach to each other and use doubled headed kinesin to move MT apart

238
Q

Intermediate Tubules structure

A

Rope like 10 nm
Not polar
2 globular ends that form coiled coil which dimerize assymetrically, and then 8 tetramers form a filament

239
Q

Epithelial Intermediate tubule

A

keratin

240
Q

Connective Tissue intermediate tubule

A

vimentin

241
Q

Nerve Tissue Intermediate tubules

A

neurofilaments

242
Q

all cells have this intermediate tubule

A

nuclear lamins

243
Q

Keratins

A

intermediate filament in the epithelium
many different variations
but liver and kidney have only 8 and 18, so these are often prone to mutation

244
Q

Lamin

A

intermediate tubules in all cells
Have a G-tain and Cap motif
There is region of prenilation that attaches a hydrophobic fatty acid tail that gets imbedded in the membrane.
Cleavage of this tail is necessary for proper lamin function

245
Q

Actin structure

A

microfilaments 5-9 nm diameter
Bound to ATP and ADP
Pola: + pomotes growth and - end is the ATP binding pocket

246
Q

Formation of Actin filaments

A

Nucleation!
G actin must bind to two other monomers - requires high concentration of monomers for them to actually bind - doesn’t happen naturally!
uses FH2 and Arp2/3

247
Q

Nucleation Factors of Actin

A

FH2 and Arp2/3
both exist in active complex are activated by small GTPase
FH2: forms actin bundles and mimics single actin
Arp2/3 forms branched actin bundles - prevalent in cell motility

248
Q

How is Actin regulated?

A

G-actin concentration; Capping proteins (gelsolin); severing/depolarization proteins, ATP/ADP exchange (profilin)

249
Q

Actin Functions

A

Epithelial cell polarity; Contraction of muscle; Cell motility; cytokinesis

250
Q

Epithelial cell polarity

A

determined by actin
Sense Function: prevents diffusion from AP to BL
Gate function: prevents diffusion through tight junctions
actin forms microvilli on AP surface (myosin V)

251
Q

Contraction of muscle

A

uses myosin with ATP hydrolysis for head stroke to ring Z lines together.

252
Q

Cell motility

A

Actin is regulated by Arp2/3 growth at one end

depolarization at the other end

253
Q

Cytokinesis

A

Forms the bundle that pinches off during cytokinesis

Rho (small GTPase) activates ROCK kinase to phosphorylated myosin to activate cytokinesis ring.

254
Q

what has abnormal cytokinesis

A

Normal, erythroblast, sperm, platelets, epithelial

255
Q

Pancrine/Autocrine

A

receptor is located on signaling cell

256
Q

Contact-dependent signaling

A

receptor on neighboring cells; contact by receptor bound mediator

257
Q

Receptor types

A

Ligand or voltage gated, GPCR, enzyme linked (tyrosine kinase), Nuclear receptors

258
Q

Lipophilic signaling molcules

A

Hydrophobic

penetrates membrane, Receptors can be intracellular, cannot be stored, controlled by synthesis, slow, steriods!

259
Q

Lipophobic signaling molecules

A

hyrophilic

cannot penetrate membrane, receptors extracellularly, can be stored in vesicles, Fast, peptides, proteins, AA

260
Q

What does signaling receptors regulate?

A

metabolic enzymes, gene regulator elements, cytoskeletal elements, exo/endocytosis proteins (insulin, NT)

261
Q

How do signaling molecules work?

A

Protein modification, protein-protein binding, GTP/GDP exchange

262
Q

Types of protein modification via signaling

A

phosphorylation, acetylation, glycosylation, ubiquitination, proteolytic cleavage

263
Q

Signaling amplification

A

signaling cascade, positive feedback loop, hormones

264
Q

Signaling termination

A

Extracellular signaling molecule diffusion, inactivation, uptake, receptor desensitization/internalization, 2nd messengers, negative feedback, enzymes to terminate siganl, GAP binding proteins

265
Q

PDE5:

A

Phosphodiesterase breaks down cGMP to GMP to terminate signal.
Cooperative binding with 2cGMP and PKG

266
Q

Stops of muscle contraction

A

1) action potential
2) depolarization
3) calcium flows into cell
4) Ach released into intermuscular junction
5) Ach binds to ACh receptor
6) inward movement of Na
7) depolarization leads to opening of dihydrohyridine recpetors
8) opesn RyR in SR to release Ca
9) Ca binds to troponin C to lead to contraction

267
Q

Signaling node

A

multiple input and output

268
Q

Signaling module

A

groups of components that function together in signalin

269
Q

Receptor Tyrosine Kinase is involved in..

A

growth, motility, metabolism, survival, differentiation

270
Q

RTK structure

A

located in PM
dimer (homo or hetero) when bound to ligand
intracellular kinase for autophosphorylation to activate downstream signals like Ras or AKt

271
Q

Ras vs AKT

A

Ras = proliferation

AKT: survival

272
Q

EGFR

A

epidermal growth factor receptor

Grb2 and Sos to activate Ras

273
Q

Grb2

A

with EGFR
adaptor protein with two domains
SH2: binds to P tyrosine
SH3: binds to proline peptides in Sos

274
Q

Sos

A

Ras GEF that binds to SH3 domain at activates RAS

275
Q

GAP

A

removes P from GTP to make GDP (inactivates) RAs

276
Q

GEF

A

exchanges GDP for GTP to activate Ras

277
Q

EGFR in cancer

A

overexpressed in breast, glioblastoma, Head and Neck, bladder, colorectal, ovarian, prostate,
larger number of ECFR correlates with poor prognosis

278
Q

EGFR inhibitors

A

Block extracellular binding site (cetuximab)

Block ATP binding site (gefitinib)

279
Q

Why do EGFR drugs become ineffective?

A

mutant kinase to stop inhibitor from binding
activation of parallel signaling pathways
cancer cells circumvent and go downstream to activate same pathway

280
Q

G protein coupled receptors structure

A

7 transmembrane helices
N-outside
C-inside
i2 and i3 loops intracellular that interact with G protein

281
Q

inactive G protein

A

BY bound to Ga-GDP

282
Q

Active G protein

A

BY repelled by Ga-GTP due to switch II

Ga GTP activates 2nd M and ion channels

283
Q

sympathetic NS recpetors

A

androgen

284
Q

parasympathetic NS receptors

A

Parasympathetic

285
Q

Beta1 receptor

A

androgen using Gs alpha
Stimulates adenylyl cyclase to increase cAMP and activate PKA to open VGCC and RyR to lead to increase calcium and increasd HR and contraction

286
Q

B1 agonists and antagonists

A

agonists: NE, E, isoproterenol
antagonists: propanolol, metoprolol

287
Q

metoprolol

A

beta blocker, decreases heart rate and contraction

288
Q

M2 Receptor

A

ACh receptor using Gialpha
Inhibits Adenylyl cyclase to decrease cAMP, decrease PKA, decrease calcium influx to decrease heart rate and contraction
BY when active activates K channel GIRK to outflow K to hyerpolarize membrane and decrease excitability

289
Q

M2 agonists and antagonists

A

Agonists: Ach, muscanin
antagonists: atropine, epinephrine

290
Q

cAMP regulation

A

degraded by Phosphodiesterases to increase AMP

291
Q

PDE inhibitors

A

caffine, theophyline, PDE3 and PDE4

292
Q

Alpha 1 receptor

A

Androgen receptor with Gqalpha
activates Phsophlipase C to cleave PIP2 into IP3 and DAG.
IP3 activates IP3 repeptor and DAG activates PKC and VGCC to increase calcium, to cause contraction of smooth muscle. decreases Blood to skin and increases BP

293
Q

alpha 1 agonists and antagonists

A

Agonists: NE, E, phenylephrine
Antagonists: prazosin

294
Q

Beta receptor in lung

A

Uses Gsalpha through PKA and inhibit smooth muscle contraction and BRONCHODILATION

295
Q

Beta receptor in lung agonsit

A

albuterol

296
Q

M3 receptor

A

ACh using GqAlpha

activates PLC and IP3 and DAG to increase Ca and contraction and Bronchoconstriction!

297
Q

M3 agonists and antagonists

A

Agonists: ACh
Antagonists: aropine, iparopium

298
Q

Desensitization of G protein coupled Receptors

A

BY interacts with GRK to facilitate
B-arrestin binds to GPCR to interalize receptor for degradation or resensitzation by phosphatase to remove B-Arrestin.
when internalized activates JNK or ERK pathway

299
Q

Classification of protein kinases

A

phosphorylated residues, substrate, activating stimulus, phylogenic relationship

300
Q

Kinase structure

A 
large lobe (helices with activation loop)
small lobe (beta sheets with glycine rich loop, helix C tht binds to glycine rich loop)
301
Q

Closed Conformation in Kinase

A

Glycine rich loops forces out Y phosphate for cleavage - Fast!

302
Q

Open conformation of Kinase

A

Glycine loop allows for exchange between ADP and ATP SLOW

303
Q

PKA

A

inhibitory protein interaction

2 catalytic subunits bound to 2 regualtory subunits that require cAMP binding for release and autophosphorylation

304
Q

CDK2

A

activating protein interaction

needs cyclin, phosphorylation of activation loop, removal of inhibitory region

305
Q

PKA is phosphorylated by…

A

PKA

306
Q

PKB (AKT) is phosphorylated by…

A

PDK1

307
Q

PKC is phosphorylated by…

A

PDK1

308
Q

CaMKI is phosphorylated by…

A

CaMKK

309
Q

CaMKIV is phosphorylated by…

A

CaMKK

310
Q

CaMKII is phosphorylated by…

A

nothing!

311
Q

Calcineurin

A

protein phosphatase 2B

converts posphoryalted NFAT into active NFAT for Translocation to nucleus

312
Q

mTOR

A

S/T kinase

activates CDK2 to to lead to proliferation

313
Q

ERK pathway of MAPKinase pathway

A

Y kinase activates PLC to increase calcium and activate calcineurin (NFATc).
Y kinase also activates Ras and MapKKK—> MAPk (erk) to be a TF NFATn
NFATn and NFATc are both required to activate and transcribe IL2 genes

314
Q

Autocrine pathway of Map Kinase

A

IL2 gene synthesis leads to activation of IL2 recpetor in PM to activate CDK2 to lead to proliferation

315
Q

Rapamycin

A

binds to FKBP to inhibit mTOR in autocrine MAP K pathway

316
Q

Cyclosproin

A

binds to cylophilin to block calcineurin and inhbit ERK pathway

317
Q

FK506

A

binds to FKBP to inhibit calcineurin (same effect as cyclosporin)

318
Q

Excitatory CNS response

A

Glutamate bidns to AMPA to lead to Na influx
NDMA is blocked by Mg, but depolarization removes mg and allows Ca influx
Ca causes potentiation of AMPA receptors through calmodulin (CaMK II)

319
Q

Calceneurin

A

low frequenzy signal leads to long term depression

320
Q

Potentiation

A

high frequency signal that leads to Calmodulin of CaMKII activation

321
Q

what is calcium used for in all cells

A

gene exp, programmed cell death, ATP synthesis

322
Q

Ca Channels located on PM

A

Voltage gaged and ligand gated
stored operated
Both take Ca from outside into cyto

323
Q

Ca Transporters on PM

A

Na/Ca exchangers (NCX) - extrude 1 Ca for every 3 Na

PMCA pumps: use ATP to move Ca outside

324
Q

Ca Channels in ER/SR

A

IP3 and RyR (in heart)

Calcium form lumen into ctyo

325
Q

CA Transporters in ER/SR

A

SERCA pump: uses ATP to move Ca from cyto into lumen

326
Q

Ca Mitochonridal pumps/trans

A

mitochonridal uniporter
permeability transition pore (MPTP)
depend on Ca gradient

327
Q

Calcium Buffer

A

restrict spacial spread of calcium - parvalbumin

temporary storage site for Ca during slow transport process

328
Q

Calcium buffers in ER/SR

A

high capacity, low affinity buffers
large amounts of Ca are stored without generation of a large gradient of free Ca
Calsequestrin

329
Q

Calcium Effectors

A

surface membrane protential, PCK, synaptotagmin, calmodulin

330
Q

PCK

A

Ca binds to C2 in PCK to associated with PM

331
Q

Synatotagmin

A

Ca binds to C2 to aid in fusion of synaptic vesicles

332
Q

Calmodulin

A

Four EF hands (Ca binding sites) that coordinate 5 Oxygen, (1 backbone, 3 Asparates, 1 glutamate)
regulates calcium reguation of ion channels, Protein kinases, PDEs

333
Q

EF hand motif

A

common in Ca effectors:
paravlbumin, Caplain( Ca activated protease)
troponin (thin filament that responds to contraction)

334
Q

SM contraction

A

maintained depolarization triggers VGCC and RyR to increase cyto Ca

335
Q

SM relaxation

A

RyR causes localized Ca to activate nearly Ca activated K channel to hyerpolarize to cause closure of VGCC and relax

336
Q

Ca in activation of T-lymphocytes

A

MHC binds to T cell receptor to rigger activation of tyrosine kinase to activate PLC and increase DAG and IP3 to cause depletion of ER Calcium. This activates stored calcium channel (orai1) to cause Ca influx.
Ca binds to calmodulin which binds to Calcineruin (phosphatse) to make NFAT active to translate IL2 genes

337
Q

Polymorphic ventricular tachycardia

A

Normally Ca released from RyR synchronizes with depolarization via Na/Ca exchangers to activate VGCC during action potential.
mutation in RyR leads to delayed Ca release and delayed depolarization by Na/Ca exchanger and no longer synchronized with AP

338
Q

Stem cell niche

A

microenvironment where stem cells are found; regualte cell fate
hormonal, metabolic, neuronal

339
Q

Rare blistering skin disorder

A

lacks collagen 7

340
Q

Adult stem cell plasticity

A

can reprogram stem cells into de-differentiated state

transdifferentiation

341
Q

Yaanaka experiment

A

took facors in embyonic cell and found that Oct 3/4, Sox2, c-Myc, and Kif4 are required for reprogramming

342
Q

Induced pluropotent stem cells

A

using own stem cells to generate embryonic stem cells, can correct mutation using genome editing

343
Q

obstacles with IPS stem cells

A

1) viral vectors - now we used modified mRNA
2) homologous recombination/gene editing
3) differentiation back into lineage (BMP4 for ectoderm)

344
Q

when is IPS used?

A

burn victim, corneal epithelium, universal donor stem cells, prevents organ rejection

345
Q

Cancer and stem cells

A

originate from epithelial stem cells

346
Q

Elements of the ECM

A

1) glucosaminoglycans
2) collagen
3) multidomain adaptor proteins

347
Q

Glucosaminoglycans

A

glycosylated protein with disaccharide motif
variable sulfation and hydroxyl groups added
attached to serine on protein, linked to GAG by tetrasaccharide linker

348
Q

Function of GAGS

A

Hydration, scaffold for proteins and molecules to bind, signaling molecule binding, prevent shearing of cells, protect against cancer progression

349
Q

How to Gags prevent shearing?

A

Gag binds to chymokines on leukocytes

high affinity binding; high off rate, acts like velcrow

350
Q

Collagen

A

homotrimer clipped at N and C domain and specially tranpsorted cross linked by aldoases to form fibers and mesh

351
Q

What type of collagen is in BL?

A

4

352
Q

multipdomain adpator proteins

A

binding sites for matrix molecuels and adhesion molecules

Fibronectin, and laminin

353
Q

Fibronectin

A

large dimeric glycoprotein linked by disulfide bonds

binds to integrins, collagen, heparin, and self

354
Q

Laminin

A

alpha, beta, gamma subunits, disulfide linkages to form helical stucture
found in basal lamina

355
Q

Types of motility

A

Round shaped - blebs

elongated

356
Q

Elongated motility

A

formation of pseudopods with removal of ECM by MMPs

357
Q

MMPs

A

cleave ECM in zinc dependent fashion; cleavage is specific; can also clave cell-cell adhesions
proMMP is inactive intracellular, but cleaved extracellular to be active
cleavage cuts GAG and leads to positive feedback loop

358
Q

integrins

A

Alph and beta forms transmembrane dimer
backed in adhesion blasts
C terminus interactis with actin via adaptors
N terminus binds to ECM
treadmilled for recycling - kinases intracellulary regualtes actin binding to integrin

359
Q

Ligation of integrins

A

promote surival by activating AKT, NFKB and decreases P53 activity.
Inhibit apoptosis

360
Q

SRC mutation

A

anchorage independence; hyperactivates invasion pathway of BL membrane

361
Q

Cadherins

A

single pass transmembrane glycoproteins that operate as homodimers in Ca dependent fasion.
Interacts with other cells to form heterotetramer in antiparallul fasion
interacts with actin via p120, alph and beta catenin

362
Q

Beta catenin

A

mutated in cancer to loose cell-cell adhesions
a TF
When bound to cadherin is inactive as TF by phosphoryaltion of AXN and APC
WNT inhibits AXN and APC phsophorylation, so B-Catenin is not degraded and promotes TF

363
Q

CAM

A

calcium indpendent cell-cell adhesion factors
monomers bind in an antiparallel way with neighboring cells
Cytoskeletal linkage, regulation of adhesion, actin polymerization, cell signaling

364
Q

how to prevent prostate cancer progression

A

castration (surgical or medical)
conadotropin releasing hormone agonist
anti-androgen

365
Q

medical castration

A

leuprolide

366
Q

how doe anti-androgens work

A

bicalutamide

competes with agonist for binding, primitive ones ended up having a activating effect somtimes

367
Q

structure of Androgen recptor

A

Transactivation omain (N), DNA BD

368
Q

AR regulation

A

sequestered in cyto by HSP

Testosterone facilitates translocation and homodimerization to promote transcirption.

369
Q

Resistance to castration

A

non-gonadal testosterone; overexpression of AR; promiscuous AR activation; truncated AR - always on!

370
Q

Testosterone creation

A

testes
5-10% adrenal
intracrine (tumor themsevles)

371
Q

Abiraterone

A

CPY17 (cyptochrome P) inhibitor; blocks creation of all types of testosterone
side effects: hypokalemia, edema, anti-androgen

372
Q

Enzalutamide

A

next gen anti-androgen
inhibits translocation, co-activator recruitment, inhibits DNA binding
no known agonist properties!

M2M Unit 3 (1 decks)

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