TUMOR SUPPRESSOR GENES & CELL CYCLE CONTROL MCQs

Question 1

What is the chromosomal location of the RB gene?

Accepted Answer

13q14 — The RB gene, the first tumor suppressor gene to be discovered, is located at chromosomal locus 13q14. ---

Question 2

According to Knudson's two-hit hypothesis, how many mutations are required to develop retinoblastoma?

Accepted Answer

Two hits (mutations) are required — Knudson's two-hit hypothesis states that two hits are required to develop retinoblastoma - both copies of the RB tumor suppressor gene must be dysfunctional. ---

Question 3

In familial retinoblastoma, what is the origin of the first hit?

Accepted Answer

One mutation is inherited (germline), second is somatic — In familial cases, one hit (mutation) is inherited in the germline and the second hit develops when the normal Rb gene is lost by somatic mutation in retinoblasts. ---

Question 4

What is the critical cell cycle checkpoint controlled by the RB gene?

Accepted Answer

G1/S transition — The Rb gene exerts antiproliferative effects by controlling the G1/S transition of the cell cycle, preventing cells from entering S phase inappropriately. ---

Question 5

In its active tumor suppressor form, what is the phosphorylation state of RB protein?

Accepted Answer

Hypophosphorylated — In its active form, Rb is hypophosphorylated and binds to E2F transcription factor, preventing transcription of genes required for DNA replication like cyclin E. ---

Question 6

What transcription factor does hypophosphorylated RB bind to?

Accepted Answer

E2F — Hypophosphorylated Rb binds to E2F transcription factor, preventing E2F from activating transcription of genes required for cell cycle progression and DNA replication. ---

Question 7

What percentage of tumors demonstrate biallelic loss of TP53?

Accepted Answer

70% — Approximately 70% of tumors demonstrate biallelic loss of TP53, highlighting its critical role as a tumor suppressor and "guardian of the genome." ---

Question 8

Which syndrome is associated with germline mutation in one TP53 allele?

Accepted Answer

Li-Fraumeni syndrome — Li-Fraumeni syndrome involves inheritance of one defective TP53 allele in the germline, with the second defect occurring in somatic cells, predisposing to multiple cancers. ---

Question 9

What is p53 commonly referred to as due to its critical role in genomic stability?

Accepted Answer

Guardian of the genome — p53 is called the "guardian of the genome" because it serves as the central monitor of cellular stress and can initiate responses to maintain genomic integrity. ---

Question 10

Which stresses can activate p53 protein?

Accepted Answer

Anoxia, oncogene signaling, and DNA damage — p53 is the central monitor of stress in the cell and can be activated by anoxia, inappropriate oncogene signaling, or DNA damage. ---

Question 11

What mechanism activates p53 in response to DNA damage?

Accepted Answer

Phosphorylation — DNA damage leads to activation of p53 by phosphorylation, which stabilizes the protein and activates its transcriptional functions. ---

Question 12

What gene does activated p53 drive transcription of to cause G1-S cell cycle block?

Accepted Answer

CDKN1A (p21) — Activated p53 drives transcription of CDKN1A (which encodes p21), a CDK inhibitor that prevents Rb phosphorylation, thereby causing a G1-S block in the cell cycle. ---

Question 13

What is the purpose of the G1-S cell cycle block induced by p53?

Accepted Answer

To allow cells to repair DNA damage — The pause in cell cycle progression allows cells time to repair DNA damage. If damage cannot be repaired, p53 then induces cellular senescence or apoptosis. ---

Question 14

If DNA damage cannot be repaired, what outcomes can p53 induce?

Accepted Answer

Cellular senescence or apoptosis — If DNA damage cannot be repaired despite the cell cycle pause, p53 induces either cellular senescence (permanent growth arrest) or apoptosis (programmed cell death). ---

Question 15

How do oncogenic DNA viruses like HPV disable RB and p53 function?

Accepted Answer

By encoding proteins that bind to RB and p53 — Oncogenic DNA viruses like HPV encode proteins that bind to RB and p53, rendering them non-functional and allowing uncontrolled cell proliferation. ---

Question 16

What percentage of pancreatic cancers have mutations in at least one component of the TGF-β pathway?

Accepted Answer

83% — In 100% of pancreatic cancers and 83% of colon cancers, at least one component of the TGF-β pathway is mutated, highlighting its critical role as a growth inhibitor. ---

Question 17

In most normal epithelial, endothelial, and hematopoietic cells, what is the effect of TGF-β?

Accepted Answer

Potent inhibitor of proliferation — In most normal epithelial, endothelial, and hematopoietic cells, TGF-β is a potent inhibitor of proliferation, transmitting antiproliferative signals. ---

Question 18

What cellular process does TGF-β activate in late-stage tumors that promotes metastasis?

Accepted Answer

Epithelial-to-mesenchymal transition (EMT) — In late-stage tumors, TGF-β signaling can paradoxically activate epithelial-to-mesenchymal transition (EMT), promoting migration, invasion, and metastasis. ---

Question 19

What does TGF-β signaling activate that has growth-suppressing activity?

Accepted Answer

Cyclins — TGF-β signaling leads to transcriptional activation of CDK inhibitors (CDKIs) with growth-suppressing activity, while also repressing growth-promoting genes like MYC and cyclins. ---

Question 20

Which genes does TGF-β signaling repress?

Accepted Answer

MYC, CDK2, CDK4, and cyclins A and E — TGF-β signaling represses growth-promoting genes such as MYC, CDK2, CDK4, and those encoding cyclins A and E, contributing to its antiproliferative effects. ---

Question 21

What cellular behavior is abolished in cancer cells, allowing them to pile on top of one another?

Accepted Answer

Contact inhibition — Contact inhibition is abolished in cancer cells, allowing them to pile on top of one another and continue proliferating despite cell-cell contact. ---

Question 22

Which molecule maintains contact inhibition and is lost in malignant cells?

Accepted Answer

E-cadherin — E-cadherin maintains contact inhibition, which is lost in malignant cells, allowing them to overcome this normal growth-limiting mechanism. ---

Question 23

What protein does the NF2 tumor suppressor gene produce?

Accepted Answer

E-cadherin — The NF2 tumor suppressor gene produces neurofibromin-2 (merlin), which facilitates E-cadherin-mediated contact inhibition. ---

Question 24

How does the APC gene exert antiproliferative actions?

Accepted Answer

By regulating destruction of cytoplasmic β-catenin — The APC gene exerts antiproliferative actions by regulating the destruction of cytoplasmic β-catenin, preventing its nuclear translocation and transcriptional activity. ---

Question 25

What happens when APC is mutated and lost?

Accepted Answer

β-catenin accumulates, translocates to nucleus, acts as growth-promoting transcription factor — With APC mutation and loss, β-catenin is not destroyed, accumulates in the cytoplasm, translocates to the nucleus, and acts as a growth-promoting transcription factor. ---

Question 26

What syndrome is associated with germline mutation of the APC gene?

Accepted Answer

Hereditary breast-ovarian cancer syndrome — Familial adenomatous polyposis syndrome involves inheritance of a germline mutation in the APC gene, with sporadic loss of the normal allele causing development of hundreds of colonic polyps at a young age. ---

Question 27

What percentage of sporadic colon cancers show somatic loss of both APC alleles?

Accepted Answer

70% — Somatic loss of both alleles of the APC gene is seen in approximately 70% of sporadic colon cancers, demonstrating its importance in colorectal carcinogenesis. ---

Question 28

What are the two main pathways that can initiate apoptosis?

Accepted Answer

Intrinsic and extrinsic pathways — Apoptosis can be initiated through extrinsic (death receptor) or intrinsic (mitochondrial) pathways, both resulting in activation of a proteolytic caspase cascade. ---

Question 29

What regulates mitochondrial outer membrane permeabilization in apoptosis?

Accepted Answer

Caspases only — Mitochondrial outer membrane permeabilization is regulated by the balance between pro-apoptotic molecules (e.g., BAX, BAK) and anti-apoptotic molecules (BCL2, BCL-XL). ---

Question 30

What is the role of BH3-only proteins in apoptosis?

Accepted Answer

Regulate balance between pro- and anti-apoptotic BCL2 family members — BH3-only proteins (BAD, BID, and PUMA) regulate the balance between pro- and anti-apoptotic members of the BCL2 family, tilting it in favor of pro-apoptotic molecules to activate apoptosis. ---

Question 31

How do BH3-only molecules activate apoptosis?

Accepted Answer

By tilting balance in favor of pro-apoptotic molecules — BH3-only molecules activate apoptosis by tilting the balance in favor of the pro-apoptotic molecules, promoting mitochondrial outer membrane permeabilization and caspase activation. ---

Question 32

What is autophagy?

Accepted Answer

Stress-induced process where cells consume their own components — Autophagy is a stress-induced process where cells consume their own components, which cancer cells may avoid through mutations or corrupt to provide parts for continued growth. ---

Question 33

How can cancer cells manipulate autophagy?

Accepted Answer

Accumulate mutations to avoid it or corrupt it to support growth — Cancer cells may accumulate mutations to avoid autophagy (which could lead to cell death), or may corrupt the process to provide cellular components for continued growth. ---

Question 34

What happens to telomeres in normal cells with each cell division?

Accepted Answer

They shorten — Telomeres shorten with each cell division in normal cells due to incomplete replication of chromosome ends, eventually activating cell cycle checkpoints leading to senescence. ---

Question 35

What is the consequence of shortened telomeres in normal cells with intact checkpoints?

Accepted Answer

Senescence — Shortened telomeres in normal cells with intact checkpoints eventually activate cell cycle checkpoints, leading to senescence and placing a limit on the number of divisions. ---

Question 36

What happens when cells have disabled checkpoints and shortened telomeres?

Accepted Answer

Massive chromosomal instability and mitotic crisis — In cells with disabled checkpoints, DNA repair pathways are inappropriately activated by shortened telomeres, leading to massive chromosomal instability and mitotic crisis. ---

Question 37

How do tumor cells achieve immortality?

Accepted Answer

By reactivating telomerase — Tumor cells reactivate telomerase, thus staving off mitotic catastrophe from critically shortened telomeres and achieving unlimited replicative potential (immortality). ---

Question 38

What is the fundamental characteristic of tumor suppressor genes?

Accepted Answer

They apply brakes to cell proliferation — The proteins encoded by tumor suppressor genes apply brakes to cell proliferation. Disruptions of such genes render cells refractory to growth inhibition. ---

Question 39

How many copies of a tumor suppressor gene must be dysfunctional for tumor development?

Accepted Answer

Both copies must be dysfunctional — Unlike oncogenes (which require only one mutated copy), both copies of a tumor suppressor gene must be dysfunctional for tumor development to occur. ---

Question 40

What is the clinical consequence of heterozygosity at the RB locus?

Accepted Answer

Not neoplastic — Heterozygosity at the Rb locus (one normal, one mutated allele) is not neoplastic. Both alleles must be lost for tumor development, illustrating the two-hit hypothesis. ---

Question 41

What cancers besides retinoblastoma show homozygous loss of RB gene?

Accepted Answer

Multiple other cancers — Homozygous loss or mutation of the Rb gene is seen in retinoblastoma and many other cancers, demonstrating its broader role as a tumor suppressor beyond its tissue of discovery. ---

Question 42

Almost all cancers have a disabled G1 checkpoint due to what?

Accepted Answer

RB mutation or mutations affecting RB function (cyclin D, CDK4, CDKIs) — Almost all cancers have a disabled G1 checkpoint due to either RB mutation or mutations in genes that affect Rb function, such as cyclin D, CDK4, and CDK inhibitors. ---

Question 43

What is the relationship between TGF-β receptors I and II in signal transduction?

Accepted Answer

They form a complex upon ligand binding — TGF-β regulates cellular processes by binding to a complex composed of TGF-β receptors I and II. Dimerization of the receptors upon ligand binding initiates the signaling cascade. ---

Question 44

In sporadic retinoblastoma, what is the origin of both hits?

Accepted Answer

Both are somatic mutations in one retinoblast — In sporadic cases, both normal RB alleles are lost by somatic mutation in one retinoblast, requiring two independent mutational events in the same cell. ---

Question 45

What members of the BCL2 family are pro-apoptotic?

Accepted Answer

BCL2 and BCL-XL — BAX and BAK are pro-apoptotic members of the BCL2 family that promote mitochondrial outer membrane permeabilization, while BCL2 and BCL-XL are anti-apoptotic. ---

Question 46

What members of the BCL2 family are anti-apoptotic?

Accepted Answer

BAX and BAK — BCL2 and BCL-XL are anti-apoptotic molecules that prevent mitochondrial outer membrane permeabilization and inhibit apoptosis, opposing the actions of BAX and BAK. ---

Question 47

What inevitably happens to polyps in familial adenomatous polyposis?

Accepted Answer

One or more evolve into colonic cancer — In familial adenomatous polyposis, patients develop hundreds of colonic polyps at a young age, and inevitably one or more of these polyps evolve into colonic cancer. ---

Question 48

Which genes does activated p53 control in response to stress?

Accepted Answer

Genes involved in cell cycle arrest, DNA repair, senescence, and apoptosis — Activated p53 controls the expression and activity of genes involved in multiple protective responses: cell cycle arrest, DNA repair, cellular senescence, and apoptosis. ---

Question 49

What is the functional consequence of RB binding to E2F?

Accepted Answer

Prevention of transcription of genes required for DNA replication — When hypophosphorylated Rb binds to E2F transcription factor, it prevents E2F from activating transcription of genes required for DNA replication, such as cyclin E, thus blocking cell cycle progression. ---

Question 50

What fundamental process in carcinogenesis involves failure of growth inhibition?

Accepted Answer

Insensitivity to growth inhibitory signals — Failure of growth inhibition (insensitivity to growth inhibitory signals) is fundamental in carcinogenesis. Disruption of tumor suppressor genes renders cells refractory to growth inhibition and mimics growth-promoting effects.

TUMOR SUPPRESSOR GENES & CELL CYCLE CONTROL MCQs

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