Unit 3 Exam Chapter (Stem Cells, Metastasis, Angiogenesis, Immunology) Flashcards
RB1 Tumor Suppressor Gene
chromosome location
13q14
RB1 Gene function
Transcription Regulation
RB1 Tumor Type
Retinoblastoma, osteosarcoma
RB1 Cancer Syndrome
Familial Retinoblastoma
RB1 Tumor Phenotype
MTC, Pituitary adenocarcinoma, pheochromacytoma
p53 chromosome location
17q11
p53 gene function
Transcription regulation
p53 tumor type
Sarcoma
Breast/brain tumors
p53 Cancer syndrome
Li Fraumeni
p53 cancer phenotype
lymphomas, sarcomas
VHL gene function
Proteolysis regulator
VHL Tumor Type
Hemangioma
Renal
pheochromacytoma
VHL Cancer syndrome
Von-Hippel Lindau
APC Gene function
Regulates Beta-Catenin Activity
APC Tumor type
Colon Cancer
APC Cancer syndrome
Familial adenomatous polyposis
APC Tumor phenotype
Intestinal polyps
BRCA1 Gene function
Transcription regulator
BRCA1 Tumor Type
Breast/ovarian tumors
BRCA1 Cancer Syndrome
Familial Breast Cancer
BRCA2 Gene function
Transcription Regulator
BRCA2 Tumor Type
Breast/ovarian tumors
BRCA2 Cancer Syndrome
Familial breast cancer
PTEN Gene function
Dual specificity phosphatase
PTEN Tumor Type
Gliobastomas
Prostate
Breast
PTEN Cancer Syndrome
Cowden syndrome
BZN
Ldd
PTEN Cancer Syndrome
Lymphoma
thyroid
endometrium
prostate
Knudson’s two-hit hypothesis and its application to tumor suppressor genes
Explains mechanisms for tumor suppressor genes
Both alleles must be mutated to trigger carcinogenesis
Explains certain individuals have an increased risk for cancer
They inhibit tumor suppressor allele
Retinoblastoma
Rare childhood cancer
1 in 20,000
Familial and Sporadic
Familial Retinoblastoma
40% of cases
Germline mutation n RB gene is passed to child, mutation is present in all cells
Affects BOTH EYES
Sporadic Retinoblastoma
60% of all cases
Individual requires 2 somatic mutations in 2 alleles
Usually affects 1 eye
What is the role of the Retinoblastoma gene in tumor suppression?
RB protein controls cell proliferationby binding E2F transcription factor
When E2F is bound to Rb, the protein cannot activate transcription genes coding for enzymes and other proteins for initiating DNA replication (NO CELL DIVISION)
What is the role of Retinoblastoma in cell division?
Leads to production of cyclin-CDK complexes which catalyze the phosphorylation of Rb protein, which results in release of E2F- results in cell division.
What is the role played by viral gene products which interfere with tumor suppressor genes?
Several DNA viruses have been shown to be carcinogenic
Papillpmavirus, Adenovirus, Herpes Virus, and Hepatitis B
Coerces the cell into S phase
Interaction of DNA Viral protein products with Rb
Adenovirus EIA, Papillomavirus E7, and SV40 Large T antigen inactivate RB
E1A and E7 use what system when interacting with Rb?
ubiquitin-proteasome system
E7 binds ubiquitin-proteasome ligase that forms
a dimer and binds to Rb
Rb is tagged for recognition by
the proteasome for degredation
Adds a ubiquitin tag
Most important tumor suppressor gene
Most commonly mutated
P63 and P73 are homologs
Protects the cell from DNA Damage
P53 Gene
P53 is known as
The guardian of the genome
is tied to many processes
What gene regulates Over 300 different genes’ promoter regions
P53 Gene
P53 is located
On chromosome 17 and contains 11 exons
P53 contains 4 domains:
Amino-terminal transactivation domain (transactivation domain and MDM2 binding site)
DNA binding domain which binds to DNA
Oligomerization domain
Carboxy-terminal (regulatory domain)
Upstream molecular pathways of P53 activation
Prevents degredation of P53 by MDM2
CHK and Casein Kinase II disrupts
P53-MDM2 by phosphorylating P53
DNA Damage-> P53 Activation
DNA Double-Stranded Breaks
DNA Damage
ATM
CHK2
P53 activation
Cell stress-> P53 Activation
Cell Stress
ATR
Casein Kinase II
P53 Activation
Downstream inhibition of the cell cycle and activation of DNA repair mechanisms
p53 suppresses tumors by
Causing cell cycle arrest
P35 acts as transcriptional activator for p21 gene
p21 acts as an inhibitor for cyclin-CDK complex, stopping cell cycle between G1-> S-> G2 -> M
P53 acts as
a transcriptional activator for P21 gene
P21 acts
as inhibitor for cyclin-cdk complex stopping cell cycle between G1 S and G2 M
P21 also binds
PCNA (Proliferating Cell Nuclear Antigen) that has a role in DNA repair
What regulates expression of XPC Gene which has a role in nucleotide excision repair (DNA repair mechanism)
P53
NOXA, PUMA, P53, A1P1
Promote apoptosis by releasing cytochrome C from the mitochondria causing cell death
____ regulates pro-apoptotic BAX and repressing Antiapoptotic BCL-2
P53
____ Regulates expression of thrombospondin, an inhibitor of angiogenesis
P53
Autoregulatory Feedback loop associated with P53 gene
A transcription factor transcribing a protein that inhibits transcription factors
Germline mutation of P53 gene
Leads to predisposition to a wide range of cancers
25-fold increased risk of developing cancer before 50 years old
Develop cancer at a young age and have frequent occurrence of multiple primary tumors
Sarcomas, Breast Cancer, Leukemia, Brain Tumors
Li Fraumeni Syndrome
Mutations of the P53 pathway and cancer (type of mutation)
Over 75% are missense mutations- different from classic tumor suppressor genes that are characterized by nonsense or frameshift mutations
More than 90% of missense mutations located in
DNA binding domain and more than 30% of these affect only 6 codons and are therefore “hotspots”
Common therapeutic strategies for treating cancers associated with tumor suppressor genes
Advexin
Onyx015
Ataluren
Nutlins
Advexin
Gene therapy
P53 Restored
Onyx 015 Virus
Viral replication, cell lysis
APR-246 and PRIMA-1
Aberrant folding
Restores P53 function
Atalauren
Read-through
Ignore the stop codon, make the normal protein
Nutlins
Binds to MDM2
Target P53 inhibitor (MDM2) and activates P53
Pifithrin-Alpha
Inhibits P53 transcription
May be used to limit side effects in normal cells
When cancer cells are not dividing, what phase of the cell cycle are they in?
G0
Cancer stem cells obligatory asymmetric replication
When a stem cell divides, it becomes another stem cell and a progenitor cell
Progenitor cell will divide rapidly, and their progeny divide and differentiate into a specific cell type
A block in cell differentiation results in
a higher net number of cells and therefore is a mechanism for tumor formation
True or False: DIfferentiated cells enter the cell cycle
FALSE
Differentiated cells withdraw from the cell cycle
Normal Cells multiply only when needed
On activation by environmental input, the niche cells induce them to divide into a stem cell and progenitor cell
Human Embryonic Stem Cells (hESC) types
Pluripotent
Ethical debate
Easy to grow and acquire
Adult stem cells
includes umbilical cord blood stem cells
Amniotic fluid stem cells
Fetal Stem cells
Fetal stem cells
Multipotent- Often used in bone marrow stem cell transplants in leukemias and lymphomas
3 types of stem cell transplants
Autologous
Allogenic
Syngenic
(Avoids ethical issues)
Autologous stem cells
your own bone marrow stem cells
More likely to avoid immune rejection
Allogenic stem cells
From an HLA matched individual
Syngenic Stem cells
From an identical twin
Induced Pluripotent Stem Cells (iPSC)
Adult cells that have been reprogrammed
Core of regenerative medicine
Pluripotent
Cancer stem cells
Rare
Located within the tumor and can self-renew
Can give rise to phenotypically diverse cancer cells
Cancer stem cell Surface Protein Markers
Breast cancer stem cell markers CD44+, CD24-low
Colon cancer stem cells over-express the surface antigen CD133
Feature of self-renewal shared with tumor cells
Self-Renewal provides increased opportunities for carcinogenic changes to occur
Altered regulation of self-renewal directly underlies carcinogenesis
Cancer stem cell signaling pathways
Wnt
Hedgehog
Wnt Pathway
Plays a role in stem cell self-renewal Stimulatory factor 19 Wt genes Involved in embryonic development (Development of the heart) Has a destruction complex
Wnt Pathway Destruction complex
Axin
APC
CKI
GSK3Beta
How is the Wnt pathway regulated in normal cells?
Wnt binds to frizzled and LRP is phosphorylated with Axin
(Activated) Beta Catenin Binds to TCF/LEF with BCL9 and pygopus
affects target genes like c-myc and cyclin
(Self-Renewal Proceeds)
When beta catenin binds to TCF, what happens?
Self-Renewal proceeds
When Beta Catenin is inhbited from binding to TCF, what happens?
No differentiation
What goes wrong in tumors?
Abnormal activation of the Wnt/β-catenin pathway promotes CSC progression and thus leads to the deterioration and metastasis of cancer
Hedgehog pathway is involved in
Embryo development Tissue Self-Renewal Tissue Repair Carcinogenesis Digit formation in mammals Neural tube, gut formation
Proteins involved in the Hedgehog pathway
Gli-1 Sufu PKA Smoothened Patched
How is the hedgehog pathway regulated in normal cells?
Cyclopamine suppresses the hedgehog pathway by inhibiting the activity of transmembrane protein SMOOTHENED
Inactivating mutations in Patched and activating mutations of Smoothened are identified in what cancer?
Basal Cell Carcinoma (BCC)
Gli-1 Expression in BCC
Posesses an activated Hedgehog signaling pathway
Gli (Zinc-Finger Transcription Factor) in Hedgehog pathway (HH ABSENT)
No hedgehog
Patched cannot bind to smoothened
Sufu binds to Gli and PKA
Target genes are inhibited in the nucleus
Gli in Hedgehog pathway (HH Present)
Hedgehog protein binds to Patched, which binds to smoothened
Sufu dissociates from PKA and Gli
Gli activates target genes
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Lynch syndrome 15% of colorectal cancers Autosomal dominant Only requires one abnormal gene AD Mutation in in DNA mismatch repair 80% progress to cancer Proximal Colon Increase the risk of other cancers
Familial Adenomatous Polyposis (FAP)
85% of colon cancers Chromosomal instability Mutation in APC on chromosome 5q Beta Catenin Normal colon progression into carcinoma 100% of the time becomes cancerous Pancolonic (the entire colon)
FAP progression to Carcinoma
Normal colon-> Loss of APC gene-> Colon at risk-> K-RAS mutation-> Adenoma-> Loss of P53 gene-> Carcinoma
Polycomb Group (PcG proteins)
Guardians of stemness Genes that control development and transcription HOX FOX PAX POU SOX
What is the role of PcG proteins in stem cell differentiation?
Stem cell differentiation is dependent on the polycomb group (PcG proteins)
Repress transcription by epigenetic modifications
Inhibit FOX and SOX
Suppress stem cell differentiation
AML translocation (t98;21)
What is the role of lineage-specific transcription factors in stem cell differentiation (AML1, Pu.1, C/EBPalpha)
Shows how little we know about stem cells
Hscs-> Pu.1-> CMPs (Myeloid pathway)-> GMPs -> Pu.1-> Monocyte
OR GMPs-> C/EBPalpha-> Granulocytes
New cancer therapeutics designed to target different aspects of differentiation pathways Cyclopamine and GDC-0499
involving administration of ABC inhibitors along with chemotherapies are being investigated
Stem cells express high levels of ATP-Binding Cassette (ABC) transporters, members of the multi-drug resistance gene family
Knudson’s Two-Hit Hypothesis (Essay Question)
Explains the mechanism of tumor suppressor genes
States that both alleles must be mutated to trigger carcinogenesis
Explains certain individuals have increased risk of cancer
They inhibit tumor suppressor allele
What are stem cells (essay question)
Cells of variable potency that can self-renew
Normally found in our bodies
Help in organ maintenance
Help in Organ repair
Somewhat committed to a cell lineage type
Have the ability to migrate to other tissues
High level of telomerase activity
Maintain a balance between self-renewal and differentiation
HPCC (Hereditary Non-polyposis colorectal cancer)
Lynch syndrome 15% of colorectal cancer Autosomal dominant inheritance pattern Only requires one abnormal gene AD Mutation in DNA Mismatch repair 80% progress to cancer Occurs in the proximal colon (Ascending, Transverse) Increase the risk of other cancers
Familial Adenomatous Polyposis Coli (FAP)
85% of colon cancers Chromosomal instability Mutation in APC on chromosome 5q Beta-Catenin Normal colon-> loss of APC Gene-> Colon at risk-> K-RAS mutation-> adenoma-> Loss of P53-> Carcinoma 100% of the time becomes cancer Pancolonic (Affects the entire colon)
