Block III week 1 Flashcards
progenitor cells vs. stem cells
cells that retain the ability to give rise to terminally differentiated cells; stem cells can also regenerate themselves
lateral inhibition
cells compete by sending out inhibitory signals to neighboring cells and alterning their developmental direction
what defines the AP axis?
sperm entry site and site of extrusion of the second polar body. polarity is determined by a region of extra-embryonic tissue called the visceral endoderm, which is at the cranial end
defining the ventral dorsal axis
embryonic face of the ICM in contact with the trophoblastl
definition of the Left/right axis
lefty1 and nodal expression on the left side imparts leftness. important in the formation of the heart tube
situs solitus: where is the heart and how does the small bowel loop?
normal configuration: heart on left, small bowel loops counterclockwise
situs ambiguus symptoms
problems with congenital heart disease, asplenia or polysplenia
homeotic mutants
when one body part develops as if it were a different body part
spacial and temporal colinearity wrt homeobox genes
basically this meanst that homeobox genes are expressed in order both spacially and temporally: 3’ end of the homeobox cluster is expressed FIRST and CRANIALLY; downstream genes are expressed LATER and CAUDALLY
Symptoms and biochemical (not genetic) causes of Angelmans
symptoms: developmental disorders and intellectual disability, lack of speech, laughter, gait disturbance, seizures, hypopigmentation.
missing UBE3A, which codes for E3 that attaches ubiquitin to proteins for degradation. too much developmental noise
Coloboma-renal syndrome
Pax2 mutation. they have off center irises
Aniridia
no iris
associated with cataracts and foveal hypoplasia
Pax6 mutation
ubiquitin pathway
ubiquitin is attached to E1 in an ATP dependent manner. E1 associates with E2 and E3 complex. ubiquitin transferred to the E2/E3 complex. target protein containing a degradation signal is bound to the E2/E3 compled and ubiquitin is added to the target. E1/ubiquitin can then add to this chain. protein is moved to the proteosome.
neurofibromatosis type I (NF1). symptoms
cafe au lait spots, freckingl, neurofibromas, iris nodules and optic gliomas, dysplastic bones
neurofibromatosis type I biochemistry
gene codes for neurofibromin. This is a GTPase activating protein (GAP). GAP inactivates ras-GTP. overly active Ras-GTP leads to a decrease in cell growth control and tumors
diastrophic dysplasia
problem with a sulfate transporter that leads to severe skeletal dysplasia
Noonan syndrome
turner-like phenotype with pulmonic stenosis and developmental delay. caused by a mutation in PTPN11. t his also helps play a role in Ras signaling. it is an example of a kinase/phosphorylase mutation
defective enzyme in SLOS
7 dehydrocholesterol reductase
genetic heterogeneity. an example
multiple genetic causes for the same syndrombe because pathways are interconnected. example is Waardenburg
4 types of waardenburg
Pax 1 and 3 mutations
or MITF, a downstream target of PAX3 important for melanocyte development and neural crest function and chochlear issues.
END3 or ENDRB: survival facotrs for migrating neural crest cells. has neurological consequences
FGF receptor structure
ligand binding domain and 3 immunoglobulin like domains that form loop structures held together by intrachain disulfide bonds between cys residues.
role of heparin sulfate in FGF and FGFR binding
FGFs near the surface bind to heparain S domain.
S domain then binds the lys rich region of the second immunoglobulin like domain on FGFRs. this helps bring FGFs and FGFRs close together
Wha would happen if you lost cys residues in the FGFR?
you wouldn’t see as many intrachain disulfide bonds, so my might see more interchain bonds and a greater affinity for dimerization among FGFRs
What do FGFs do at cranial sutures?
increase osteoblast activity
dolicephaly or scaphocelphaly
premature sagittal suture- elongated head shape
trigonocephaly
premature metopic suture closure (between the frontals). anterior head narrowing
brachycephaly
both coronal or lamboids close. lateral widening, shorta anterior/posterior diameter.
plagiocephaly
single coronal or lamboid suture closure leading to asymmetric head shortening.
Apert syndrome
cranisyntosis, syndactyly, heart disease, FGFR2 mutation
Pfeiffer syndrome
craniosynotosis, prominent thumbs and big toes, distinctive facial features caused by FGF3 mutation
achondroplasia protein mutation
FGFR3 problems
thanatophoric dysplasia
causes stillbirths and infant deaths because of resp failure.
leukocoria
common clinical finding of retinoblastoma, though not required
Li-Fraumeni syndrome
SBLA cancer (sarcoma, leukemia, breast, adrenal gland) cancer syndrome
mutation of TP53 gene
dominant disorder
involves cancer diagnosis before 45, one first degree and one other first or second degree relative with cancer diagnosis
aggressive screening
Ataxia telangiectasia
involved with ATM gene. ATM phosphorylates p53 and BRAC1. it is important in the G1/G2 and G2/M checkpoints
ataxia telangiectasia is autosomal recessive disease
symptoms: progressive cerebellar ataxia, abnormal eye movements, oculocutaneous telangiectasia (often mistaken for CP); immune defects sinopulmonary tract
ends with dysarthria and dysphagia in 20s
Chronic myelogenous leukemia
Often associated with ABL gene translocations to much more constiutively expressed chromosomes. Philadelphia chromosome is a t9:22 translocation.
fatigues is most common complaint
HER-2 or ERBB-2
receptor tyrosine kinase gene
proto-oncogene
often associated with breast and ovarian cancers
pathway: epidrmal growth factor signaling
target of trastuzumab
trastuzumab
HER-2 receptor monoclonal antibody for breast cancer. modest survival increase but also have large costs and cardiotoxicity
imatinib
Bcr-abl tyrosine kinase inhibitor that is super helpful against chronic myelogenous leukemia with Philadelphia chromosome.
RET
cancer type: medullary thyroid carcinoma
cancer predisposition syndrome: multiple endocrine neoplasia type 2
molecular function: receptor tyrosine kinase
pathway: glial0-derived neurotrophic growth factor pathway (GDNF)
proto-oncogene
fain of function leads to oncogenesis; loss of function leads to Hirschsprung disease (colon immobility)
MYC
cancer type: lymphomas, neuroblastoma, and small cell lung carcinoma
molecular function: transcriptional regulators
pathway: many
proto-oncogene
importance: c0myc activation via chromosomal translocations found in Burkitt’s lymphoma, Nymic amplification in neuroblastoma is associated with poor prognosis, L-myc gene amplification found in many small cell lung carcinomas
BCL2
Cancer: B cell lymphoma molecular function: anti-apoptosis pathway: apoptosis proto-oncogene activated in B cell lymphoma due to a chromsomal translocation
RAS
cancer: many, esp. pancreatic and colorectal, myeloid leukemia, and bladder
molec function: signal regulator
pathway: signal pathways, esp. receptor tyrosine kinases
proto-oncogene
ABL
cancer: chronic myelogenous leukemia
molec function: non-receptor tyrosine kinase
proto-oncogene
Bcr-Abl in crhomsomes 9 and 22 in philadelphia chromosome
imatinab/gleevac is a targeted therapy
RB
cancer: retinoblastoma, osteosarcoma
syndrome: familial retinoblastoma
cell cycle regulator
tumor suppressor
un-phosphorylated pRB binding to E2F represses the expression of genes needed for the F to S progression of the cell cycle
TP53
many cancers
Li-Fraumeni Syndrome
function: transcriptonal regulator/pro-apoptotic protein
involved in cell cycle progression, apoptosis, metastisis
tumor suppressor gene
APC
cancer: colorectal
cancer-predispostion: familial polyposis (APC)
molecular function: signal regulator, mitotic spindle binding protein
pathway: Wnt; cell cycle
Tumor suppressor
mutated in most colorectal cancers
Wnt
- Signaling glycoprotein that binds the frizzled family of cell surface receptors
- Frizzled associates with LDL receptor related proteins (LPR). Together, they form a complex.
Canonical pathway and beta catenin
a. Cytoplasmic beta catenin usually associates with a complex made of GSK-3beta, APC protein, and a scaffold.
b. Complex phosphorylates cytoplasmic beta catenin
c. Phosphorylation is a signal leading to ubiquitinyation and protein degradations
d. When bound to Wnt, frizzled-lrp is activated, which activates protein Dishevelled
e. Dishevelled inhibits the activity of GSK-3beta, so beta catenin sticks around.
f. Beta catenin gets to the nucleus and activaes target genes by displacing protein Groucho and facility the regulatory protein LEF1/TCF
g. Target gene includes c-myc
h. APC mutations independence from Wnt signal and uncontrolled cell growth
NF1
cancer: neurofibrosarcoma, brain tumors
predisposition syndrome: neurofibromatosis type I
molec function: signal regulator
pathway: receptor tyrosine kinases
tumor suppressor
remember, it is an activator of the GAP needed to inactivate ras by taking away GTP
NF2
cancer: acoustic neuroma, meingioma, glioma, schwannoma
predisposition syndrome: neurofibromatosis type 2
molec funtion: cytoskeletal protein
pathway: cell adhesion
effect: tumor suppressor
mutation leads to loss of coordination btw growth factor signaling and cell adhesion
CDKN2A
cancer: melanoma, glioma, leukemia, bladder cancer, head and neck cancer
predisposition syndrome: familial melanoma
function: cell cycle inhibitor
pathways: cell cycle progression
effect: tumor suppressor
WT1
Cancer: Wilms
predisopostion: familial wilms tumor, WAGR, denys-drash
molec function: transcriptional regulator
tumor suppressor
deleted as part of the contingous gene syndrome WAGR (wilms tumor, aniridia, gential hypoplsia, retardation);
PTCH (patched)
cancer: basal cell carcinoma, medulloblastoma
predisposition: basal cell nevus syndrome aka gorlin syndrome
function: cell surface receptor
pathwya: Shh
effect: tumor suppressor
VHL
cancer: renal, pheochromocytoma
predisposition syndrome: Von Hippel-Lindau
function: ubiquitin ligase complex
pathwya: angiogenesis (prevents HIF-1 accumulation)
tumor suppressor
Von Hippel Lindau is an autosomal dominant syndrome of cerebral heangioblastoma, retinal angioma, and renal cysts and carcinoma
CDH1 (e-caherin)
cancer: gastric
predisposition: familial gastric cancer
function/pathway: cell adhesion
tumor suppressor
loss of function occurs late in many cancers to allow for invasion and metastisis
BRCA1
cancer: breast, ovarian, prostate, pancreatic
predisposition: familial breast and ovarian cancer
function: mediator of ds break repair and transcription
tumor suppressor gene/dna repair gene
BRCA2
cancer: breast and ovary, pancreatic and prostate
familial breast and ovarian cancer
ds break repair and transcription regulation
homozygous mutation causes faconi pancytopenia syndrome, which consists of pancytopenia, radial anomaly, short stature, and increased leukemia risk.
ATM
cancer: lymphoma
predispositon: ataxia telangiectasia
function: protein kinase; mediator of ds break repair
pathway: dna repair and cell cycle progression
phosphorylates p53 and BRCA1. homozygous mutation leads to ataxia telangiectasia
MLH1, MSH2, MSH6, PMS2
cancer: colorectal and GI, endometrial, ovarian, biliary
syndrome: Lynch/HNPCC
function: mismatch repair
