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CMBM Exam 5 > Oncogenes and Tumor Suppressors > Flashcards

Oncogenes and Tumor Suppressors Flashcards

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
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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

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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
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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
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5
Q

Myc Gene

A
  • Gene most commonly involved
  • Normally an early response gene- induced when cells are signalled to divide
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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**

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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
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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

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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

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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

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11
Q

Treatment for CML

A
  • Imatinib Mesylate (Gleevec) appears to be able to cure disease
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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)
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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
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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
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15
Q

p53 gene

A
  • Tumor suppressor gene
  • Cell cycle arrest in G1
  • Inhibit DNA replication and helicase activity
  • Inhibit Rb expression
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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
Q

Telomerase activity

A
  • 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

CMBM Exam 5 (11 decks)

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