USMLE PRACTICE QUESTION #132
TOPIC: Cell Cycle Regulation
USMLE practice question #132 will test your understanding of cell cycle regulation and principles.
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A 45-year-old man presents to his primary care physician for evaluation of unintentional weight loss and fatigue over the past two months. Imaging reveals a mass in the colon, and biopsy confirms adenocarcinoma. Genetic analysis of the tumor reveals a loss-of-function mutation in the TP53 gene. Which of the following best explains the molecular consequence of this mutation in tumor cells?
A) Increased cyclin-dependent kinase inhibition
B) Impaired activation of DNA repair mechanisms during the G1 phase of the cell cycle
C) Loss of transcriptional repression of proto-oncogenes
D) Reduced ability to induce apoptosis
E) Overactivation of the retinoblastoma protein
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the molecular consequence of this mutation in tumor cells?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Recognize the molecular cause of the patient’s findings; 2nd: Identify the correct answer choice based on the given information.
Step 3: Read the vignette carefully and ask yourself: “Based on the presentation and given information, the molecular consequence of this mutation in tumor cells is __________________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 45-year-old man presents with colon adenocarcinoma and a loss-of-function mutation in the TP53 gene—a critical tumor suppressor. The TP53 gene encodes the p53 protein, often referred to as the "guardian of the genome," because it regulates cellular responses to stress, such as DNA damage, hypoxia, and oncogene activation.
ANSWER CHOICES:
CHOICE A: Increased cyclin-dependent kinase inhibition
Explanation: CDK inhibition by p21 is one of the mechanisms by which p53 induces G1/S cell cycle arrest in response to DNA damage. Loss of TP53 function would reduce CDK inhibition, not increase it. This would lead to unchecked cell cycle progression, but this is not the primary mechanism driving tumorigenesis in TP53-mutant cells.
CHOICE B: Impaired activation of DNA repair mechanisms during the G1 phase of the cell cycle
Explanation: p53 activates DNA repair pathways by inducing transcription of genes like GADD45 and others involved in repairing damaged DNA. Loss of TP53 impairs these mechanisms, allowing mutations to accumulate. While impaired DNA repair contributes to genomic instability, this is not the primary molecular consequence of TP53 loss-of-function mutations that drive tumorigenesis.
CHOICE C: Loss of transcriptional repression of proto-oncogenes
Explanation: p53 does not primarily function as a repressor of proto-oncogenes. Instead, it acts as a transcriptional activator for genes involved in cell cycle arrest, apoptosis, and DNA repair. Loss of TP53 does not directly lead to derepression of proto-oncogenes; rather, it allows cells with damaged DNA to evade apoptosis and proliferate.
CHOICE D: Reduced ability to induce apoptosis
Explanation: One of the primary functions of p53 is inducing apoptosis in cells with irreparable DNA damage by activating pro-apoptotic genes like BAX and PUMA. Loss-of-function mutations in TP53 impair this ability, allowing cells with significant genetic damage to survive and proliferate. This evasion of apoptosis is a hallmark of cancer.
CHOICE E: Overactivation of the retinoblastoma protein
Explanation: Rb protein regulates the G1/S checkpoint by inhibiting E2F transcription factors. Overactivation of Rb would suppress cell cycle entry rather than promote it. Loss-of-function mutations in TP53 do not directly affect Rb; instead, they impair apoptosis and other tumor-suppressive functions.
FINAL VERDICT…
CORRECT ANSWER: D) Reduced ability to induce apoptosis
p53 promotes cell cycle arrest, DNA repair, senescence, or apoptosis in response to cellular stress. Loss-of-function mutations in TP53 impair its ability to activate pro-apoptotic genes like BAX and PUMA in response to cellular stress or DNA damage. This allows cells with significant genetic abnormalities to evade apoptosis and continue proliferating, contributing to tumor growth and progression.
KEY CONCEPTS:
Role of Wild-Type p53 (Tumor Suppressor):
Activates transcription of genes involved in:
Cell cycle arrest (e.g., via p21).
DNA repair (e.g., via GADD45).
Apoptosis (e.g., via BAX, PUMA).
Prevents propagation of cells with damaged DNA.
Consequences of TP53 Loss-of-Function Mutations:
Impaired apoptosis → Cells with damaged DNA evade programmed cell death.
Genomic instability → Accumulation of additional mutations.
Tumor progression → Uncontrolled proliferation despite cellular stress or damage.
Mechanisms Driving Tumorigenesis in TP53-Mutant Cells:
Evasion of apoptosis is a hallmark.
Failure to induce senescence or cell cycle arrest.
Resistance to chemotherapy due to inability to undergo apoptosis.
Clinical Relevance:
TP53 mutations are associated with poor prognosis and resistance to therapy.
Restoring wild-type p53 function is an area of active research for cancer treatment.
See ya tomorrow 👋