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Biochemistry > Molecular Biology of Cancer > Flashcards

Molecular Biology of Cancer Flashcards

1
Q

Cancer

A

Disease characterized by loss of regulation of the cell cycle, normal checkpoints are bypassed, allowing defective DNA replication and cell division, greater frequency of aneuploidy

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2
Q

Causes of cancer

A

Mutations lead to uncontrolled proliferation of cells, occur as a result of ionizing and UV radiation, chemicals, spontaneous errors during replication

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3
Q

Normal detection of mutations

A

Cell has mechanisms for detecting mutations and halting genetic processes until corrections are made, if the mutation is severe, the cell undergoes apoptosis

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4
Q

Uncontrollable growth

A

Mutated cells proliferate and develop further mutations, tumor becomes most dangerous when it gains the ability to invade surrounding tissues and proliferate in distant sites (metastasis)

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5
Q

Defects in DNA repair

A

BRCA-1,2, causes breast, ovarian, and prostate cancer, repair by homologous recombination

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6
Q

Differences between normal cells and malignant cells

A

Infinite proliferative capacity, anchorage independent, resistant to growth inhibition, resistant to apoptosis, show signs of de-differentiation, can be metastatic

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7
Q

Oncogenes

A

Result from gain-of-function mutations of growth-promoting genes, corresponding normal gene is a proto-oncogene

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8
Q

Tumor suppressor genes

A

Normal genes that encode growth-inhibiting products that become inactivated in cancer cells (loss-of-function), inhibition of growth-inhibiting activities results in unregulated cell growth

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9
Q

Varmus and Bishop

A

Hypothesized that cancer is caused by mutations in cellular genes (not viruses), many v-onc have been isolated from retroviruses, cellular proto-oncogenes (c-onc) have been found

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10
Q

Classes of cellular proto-oncogenes (c-onc)

A

Cellular growth factors, hormone and growth factor receptors, signal transduction proteins, GTP-binding proteins, nonreceptor protein kinases, transcription factors

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11
Q

Cell cycle

A

Activated by growth factors, hormone messengers, work through cyclins and cyclin-dependent kinases (CDKs), regulated by phosphorylation and cyclin-dependent kinase inhibitors (CKIs)

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12
Q

Conversion of proto-oncogene to oncogenes

A

Radiation or chemical mutagen, gene rearrangement- places proto-oncogene under control of strong transcriptional activator and fuses with with another protein, gene amplification

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13
Q

Mitogen activated protein kinase pathway

A

MAP kinase pathway activates transcription of myc and fos, phosphorylates AP-1 (fos and jun)

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14
Q

Ras

A

Monomeric G-protein in the cascade mediating cell growth/mitosis control by growth factors

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15
Q

Ras activation

A

Growth factors bind to receptors, relay signal to intracellular GTPases (like Ras), Ras becomes activated by binding GTP

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16
Q

Effect of stimulation of Ras

A

Stimulates phosphorylation cascade (MAP kinase cascade) that leads to activation of nuclear proteins that activate transcription, cell cycle is activated

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17
Q

Ras activation of the cell cycle

A

Mutations cause Ras to remain in active (GTP-bound) conformation leading to oncogenesis, Ras mutations are found in 20-25% of human tumors and up to 90% of specific tumor types

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18
Q

Neurofibromin (NF-1)

A

NF-1 activates Ras GTPase, NF-1 is a tumor suppressor, mutations in NF-1 cause neurofibromatosis

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19
Q

Retinoblastoma

A

Tumors from embryonic neural retina, occurs in young children, led to isolation of retinoblastoma suppressor gene Rb-1

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20
Q

Retinoblastoma protein (Rb)

A

Tumor suppressor product of the retinoblastoma gene, protein that functions as a negative regulator of cell cycle, arrests cells in G1 phase, halts cell proliferation

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21
Q

Action of retinoblastoma protein (Rb)

A

Binds to transcription factors (E2F1), unphosphorylated during the G0 and G1 phases, multiply phosphorylated during S and G2/M phases

22
Q

Rb and the cell cycle

A

Binds and inactivates E2F (initiates the G1/S cell cycle transition), Rb controls a crucial cell cycle checkpoint- G1/S

23
Q

Key regulators of cell cycle

A

p16/INK4, cyclin D, CDK4, Rb, at least one is dysregulated in vast majority of human cancers

24
Q

p53

A

Transcription factor regulating cell cycle, DNA repair, and programmed cell death, senses DNA damage or hypoxia

25
Q

Actions of p53

A

Upon sensing DNA damage it: halts cell cycle so new DNA synthesis will not replicate damaged DNA, up-regulates genes involved in DNA repair, and stimulates apoptosis if damage is severe

26
Q

p53 mutation

A

Most frequent mutation leading to cancer

27
Q

Li Fraumeni syndrome

A

Genetic defect in p53 leads to a high frequency of cancer in affected individuals

28
Q

p27

A

Inhibits cyclin and Cdk, blocking entry into S phase, used for breast cancer prognosis, reduced levels of p27 predict poor outcome for breast cancer

29
Q

Role of cell adhesion

A

Cadherins bind cells together, anchored by catenins and actin, loss of E-cadherin allows detachment and metastasis, catenins also function as transcription factors

30
Q

CDH1

A

Mutation in E-cadherin- diffuse gastric cancer

31
Q

APC

A

Adenomatous polyposis coli, inhibits beta-catenin, mutations cause sporadic colon cancer, inherited mutations cause familial adenomatous polyposis (FAP)

32
Q

Apoptosis

A

Programmed cell death, cells are no longer needed, executed by caspases

33
Q

Activation of caspases

A

Activated by ligands, such as tumor necrosis factor (TNF) binding the death receptor or by cytochrome c from mitochondria

34
Q

Death receptors

A

Fas/CD95, TNF-receptor 1 (TNF-R1), death receptor 3 (DR3)

35
Q

Death receptor pathway

A

Activated receptor binds two inhibitor caspases (8, 10) which activate each other, they activate execution caspases (3, 6, 7), caspase 3 activates a Bcl-2 family member Bid which affects mitochondrial integrity

36
Q

Activation of caspases

A

Synthesized as inactive precursors called procaspases, once activated they cleave other procaspases to activate them, resulting in amplifying proteolytic cascade

37
Q

Activation of apoptotic procaspases

A

Activated by an apoptosome composed of cytochrome c and Apaf-1 (pro-apoptotic protease activating factor-1)

38
Q

Bcl-2 family proteins

A

Signal integration, 30 homologous proteins with BH domains, 4 BH domains = anti-apoptosis, 3 BH = form channels, 1 BH = pro-apoptosis

39
Q

Philadelphia chromosome

A

Results from translocation between the long arms of chromosome 9 and 22, creates Bcr-Abl fusion protein, Abl is tyrosine kinase (proto-oncogene) and part of signaling cascade, when fused with Bcr it is always active, can lead to chronic myelogenous leukemia (CML)

40
Q

Burkitt’s lymphoma

A

Caused by oncogenic transformation due to translocation, causes c-myc gene to be controlled by the promoter for immunoglobulin heavy chain gene, c-myc is transcription factor, synthesized at high levels induces proliferation of white blood cells

41
Q

N-myc amplification

A

Amplified in neuroblastoma, occurs as double minutes, chromosomally integrated homogenous staining region (HSR)

42
Q

Nonsurgical cancer treatment- target DNA replication

A

Anti-folates, base analogues, alkylating agents, ionizing radiation

43
Q

Anti-folates

A

Target thymidylate synthase, purine synthesis, ex- methotrexate)

44
Q

Base analogues

A

Target thymidylate synthase, ex- 5-Fluorouracil

45
Q

Alkylating agents

A

Damage DNA, triggers apoptosis, ex- cyclophosphamide, cisplatin, cancer cells with inactive p53 proteins can avoid apoptosis

46
Q

Ionizing radiation

A

Damages DNA, triggers apoptosis, cancer cells with inactive p53 proteins can avoid apoptosis

47
Q

Nonsurgical cancer treatment- interfere with mitotic apparatus

A

Microtubule depolymerizing drugs (vinblastine), microtubule polymerizing drugs (taxol), inhibit microtubule function during mitosos of the cell cycle, causing mitotic arrest

48
Q

Nonsurgical cancer treatment- choke off blood supply

A

Drugs that block angiogensis, drugs blocking VEGF (Avastin)

49
Q

Nonsurgical cancer treatment- target oncogenic proteins with inhibitors

A

Monoclonal antibodies (herceptin- blocks Her2 receptor, Her2 overexpressed in breast tumors), active site inhibitors (Gleevec- binds active site of Bcr-abl tyrosine kinase and inactivates it)

50
Q

Important tumor suppressor genes

A

Normally control cell cycle and proliferation, Rb, CDK inhibitors (p21, p27, INK4/p16)

51
Q

Important oncogenes

A

Enhance cell proliferation when activated, Ras, myc, abl

52
Q

Important DNA repair genes

A

Help maintain integrity of genome, BRCA1, BRCA2, mismatch repair genes

Biochemistry (18 decks)

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