Oncogenes and Tumor Suppressors Flashcards
(25 cards)
1
Q
Actions of Oncogenes
A
- Growth promoting genes
- Phosphorylation of serine, threonine and tyrosine
- Activation of GTPases
- Control of DNA transcription
- Changes in the structure of a gene- result is synthesis of abnormal gene product w/ aberrant function
- Changes in regulation of gene expression- result is enhanced or inappropriate production of structurally normal protein
2
Q
Mechanisms of cancer growth following non-lethal genetic damage
A
- Mutations in genes encoding growth factors
- Over expression of growth factor receptors
*may be due to gene amplification; eg 3 members of the EGF receptor family are commonly involved
1) c-erb-B1 over expressed in 80% of lung carcinomas
2) c-erb-B2 (c-neu) amplified in high % of adenocarcinomas of breast, ovary, lung
3) c-erb-B3 overexpressed in breast cancers
3
Q
Ras family role in cancer
A
- Family of guanine triphosphate (GTP)- binding proteins
- 10-20% of all human tumors have mutant ras
- Mutation of the ras gene is the single most common abnormality of dominant oncogenes in human tumors
- Ras oncogene mutations result in decreased GTPase activity; leads to poor stimulation of GTPase activity by GAPs; ras stays in active GTP-bound form
- 90% of pancreatic adenocarcinomas contain ras point mutation
4
Q
Ras signaling pathway
A
- In inactive state, ras binds GDP- upon growth factor stimulation, ras is activated by exchanging GDP w/ GTP
- Actiavated ras excites MAP kinase pathway by binding to raf-1- excited MAP kinases activate nuclear transcription factors to initiate mitogenic response
- GAPs bind ras to increase GTPase activity of ras- in mutant ras, GAPs still bind but do not increase GTPase activity
- Ras also has some control on level of cyclin-dependent kinases to effect cell cycle regulation directly
5
Q
Myc Gene
A
- Gene most commonly involved
- Normally an early response gene- induced when cells are signalled to divide
6
Q
Proteins that help to control Myc activity
A
- Bind to DNA
- myc-max heterodimers- STIMULATE transcription
- max-max homodimers- are inactive
- mad-max heterodimers- REPRESS transcription
**Transcriptional activation of c-myc thus is regulated by the levels of myc, and mad/max**
7
Q
Cyclins and Cyclin-Dependent Kinases role in cancer
A
- Mutations of genes encoding these are found in several human cancers
- Cyclin D and CDK4 are overexpressed in many cancers- more so than any other cyclins and CDKs
8
Q
Rb encoded protein
A
- Located in the nucleus
- Underphosphorylated (active form) in G0 and G1
- Hyperphosphorylated (inactive form) in S, G2, and M
**Phosphorylation is a function of cyclin-dependent kinase activity and pRb is phosphorylated by cyclinD/CDK4, CDK6, and cyclin E/CDK2 complexes
9
Q
Oncogene cancer activation
A
- Changes in the structure of a gene- result is synthesis of abnormal gene product w/ aberrant function
- Changes in regulation of gene expression- result is enhanced or inappropriate production of structurally normal protein
1) Point mutation
2) Chromosomal Rearrangements
*Translocations- common
*Inversions- less common
3) Gene amplification
10
Q
Chronic Myelogenous Leukemia genetic mutation
A
- Breakpoint on chromosome 22 at the break point cluster region (bcr)- fusion with abl fragments
*results in amplified tyrosine kinase activity
11
Q
Treatment for CML
A
- Imatinib Mesylate (Gleevec) appears to be able to cure disease
12
Q
Imatinib Mesylate MOA
A
- Appears to cure CML
- Molecule fits into the active site of the ABL protein preventing ATP from binding there. W/o ATP as a phosphate donor, the ABL protein cannot phosphorylate is substrate(s)
13
Q
Haploinsufficiency
A
- In some cancers, tumor suppressors are not mutated
- Output of these genes is reduced- thus pushing cells towards malignancy
- Observed for more than a dozen tumor suppressor genes
14
Q
Rb gene
A
- Tumor suppressor gene
- First tumor suppressor gene discovered
- pRb- a nuclear protein- key role in cell cycle- active state is underphosphorylated
- Active state serves as a break from G1 to S
- Phosphorylation inactivates pRb
- S phase will ensue, during M pRb again dephosphorylated
- In hypophosphorylated form- pRb binds to the E2F transcription factor- together bind to DNA to inhibit S phase genes
- Upon deletion or mutation, E2F is released- binds to E2F responsive genes- cell cycle is activated
15
Q
p53 gene
A
- Tumor suppressor gene
- Cell cycle arrest in G1
- Inhibit DNA replication and helicase activity
- Inhibit Rb expression
16
Q
p21 (Waf1/Cip1)
A
- Tumor suppressor gene
- Cyclin dependent kinase inhibitor at G1
- p21 gene induced by p53 gene in response to DNA damage
17
Q
BRCA-1/2 genes
A
- Tumor suppressor gene
- BRCA-1 on chromosome 17
- BRCA-2 on chromosome 13
- Assoc. w/ breast, ovarian, colon, prostate cancer
- Inherited mutations increases susceptibility to brease cancer
- Germ line mutation- greater susceptibility of epithelial ovarian cancer
- ~5-10% of breast cancer is familial- 80% due to mutations of these two genes
- Functions are for DNA repair- binds to protein coded by RAD51 gene to fix DNA
18
Q
APC gene
A
- Tumor suppressor gene
- Germ line mutation of APC found on chromosome 5- assoc. w/ benign tumors, but ones that are precursors of carcinomas that later develop
- Individuals w/ one mutant allele- numerous polyps found in colon in teens and twenties
- Both copies of gene must be mutated to get tumor development- first tumors are adenomas- more mutations are required to get carcinoma
- 70-80% of non-familial colorectal carcinomas and sporadic adenomas show homozygous loss of the APC gene
- Disease-assoc. mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product
19
Q
Beta catenin
A
- Released and accumulates when APC is inactivated
*result is increased binding to the TCF transcription factor to increase gene transcription
20
Q
NF-1 gene
A
- Tumor suppressor gene
- Behaves similar to APC- both alleles mutated will give rise to benign neurofibromas- a condition called neurofibromatosis-1- these can later develop into neurosarcomas
- Children w/ the disease have increaed risk of acute myeloid leukemia
- Encodes neurofibromin protein which regulates ras
*acts as a GTPase activating protein (GAP)- facilitates conversion of active ras to inactive ras
*loss of NF-1, ras stays active
21
Q
Oncogene and Tumor Suppressor Genes during cancer development
A
22
Q
Genes Regulating Apoptosis
A
- bcl-2, bcl-x (anti-apoptotic)
- bax, bad, bid, bcl-xS (pro-apoptotic)
- These genes govern mitochondrial outer membrane permeability- release or maintenance of cytochrome C
- Pro-apoptotic- activate through caspase-9 and 3
23
Q
PTEN gene
A
- Common alteration seen in a range of different advanced cancers
- Linked w/ cell regulation and apoptosis
- PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor is PI (phosphoinositide) that can inhibit cellular proliferation, survival and growth by inactivating PI3-kinase-dependent signaling. It also suppresses cellular motility through mechanisms that may be partially independent of phosphatase activity
24
Q
PTEN gene mutation cancer
A
- Mutations in the gene are documented in cancer of the breast, prostate, endometrium, ovary, colon, melanoma, glioblastoma and lymphoma
- Animal models show that the loss of just one copy of the gene is enough to interrupt cell signalling and begin the process of uncontrolled cell growth
25
Telomerase activity
- Inactive in normal somatic cells
- Some cancers become immortalized b/c they express telomerase and can continue to proliferate indefinately
- Some lung cancers express telomerase and some studies suggest that expression is an adverse prognostic factor
