A researcher adds a drug that permanently blocks ubiquitin-mediated protein degradation in a cycling cell. What is the most likely consequence for cell cycle progression?
AThe cell cycle accelerates because protein synthesis can now outpace degradation
BThe cell arrests at the next phase transition because cyclin levels cannot fall, preventing the reset required for checkpoint passage
CThe cell skips directly to mitosis because CDKs accumulate without inhibition
DNothing changes because cyclin synthesis rates, not degradation, control the cycle
Cell cycle progression depends on cyclin levels rising AND falling. Cyclins drive the cycle forward when they accumulate; the cycle advances to the next phase when cyclins are destroyed via ubiquitin-mediated proteolysis. For example, cyclin B must be degraded to exit mitosis. If degradation is blocked, cyclin levels can never fall, the cell becomes trapped — unable to complete the current phase and reset for the next. This reveals the key principle: the cycle is controlled not just by turning genes on but by regulated protein destruction.
Question 2 Multiple Choice
In a cancer cell, a mutation causes the Rb protein to be constitutively phosphorylated (permanently in the inactive, phosphorylated state). What is the expected consequence?
AThe cell permanently arrests in G1 because Rb cannot be activated to release E2F
BThe cell bypasses the G1 restriction point and enters S phase without requiring growth factor signals
CCDK4/6 activity increases to compensate for the non-functional Rb
Dp53 is upregulated to compensate, preventing uncontrolled proliferation
Rb normally sequesters the transcription factor E2F in its hypophosphorylated state, blocking expression of S-phase genes and acting as the G1 gatekeeper. Phosphorylation of Rb by cyclin D-CDK4/6 and cyclin E-CDK2 releases E2F, committing the cell to S phase. If Rb is constitutively phosphorylated (always inactive), E2F is permanently free and continuously drives S-phase gene expression — the cell enters S phase without requiring the growth factor signals that normally trigger cyclin D synthesis. This is one of the most common mechanisms of tumor suppressor loss in cancer.
Question 3 True / False
CDK proteins are inactive during most of the cell cycle because they are mainly synthesized during the specific phase when they are needed.
TTrue
FFalse
Answer: False
This is the key misconception about CDK regulation. CDK protein levels remain relatively constant throughout the cell cycle — they are not regulated at the level of synthesis or degradation. CDKs are inactive because they require a cyclin partner to become catalytically active. It is the cyclins that oscillate: they are synthesized at specific phases and then rapidly destroyed by ubiquitin-mediated proteolysis. Cyclin binding changes the CDK's conformation, activating its kinase activity. The cycle is driven by waves of cyclin availability, not waves of CDK expression.
Question 4 True / False
The spindle assembly checkpoint can halt anaphase if even a single chromosome is not properly attached to spindle fibers from both poles.
TTrue
FFalse
Answer: True
The spindle assembly checkpoint (SAC) monitors kinetochore attachment and monitors that each chromosome is bi-oriented — attached to spindle fibers from opposite poles (amphitelic attachment). A single unattached or incorrectly attached kinetochore generates an inhibitory 'wait' signal (through the MCC — mitotic checkpoint complex) that prevents activation of the APC/C ubiquitin ligase. Without active APC/C, securin and cyclin B cannot be degraded, anaphase cannot begin, and sister chromatids cannot separate. This all-or-none vigilance prevents aneuploidy — the gain or loss of chromosomes that can lead to cell death or cancer.
Question 5 Short Answer
Why does cancer typically require mutations in multiple cell cycle regulatory genes rather than just one, according to the multi-hit hypothesis?
Think about your answer, then reveal below.
Model answer: Because cell cycle checkpoints are layered and redundant. A single mutation that activates a proto-oncogene (e.g., amplifying cyclin D) may trigger p53-mediated arrest or apoptosis before a tumor develops — the other checkpoints compensate. A single tumor suppressor loss (e.g., p53 mutation) alone may not be sufficient to drive uncontrolled proliferation if other controls (Rb, SAC) remain functional. Full bypass of cell cycle control typically requires mutations in both accelerators (oncogenes) and brakes (tumor suppressors), plus often mutations that disable apoptosis pathways. Since each required mutation is a rare stochastic event, cancer incidence increases dramatically with age as mutations accumulate over time.
This connects the molecular machinery to cancer epidemiology. The multi-hit model explains both why cancer is relatively rare (multiple independent rare mutations required) and why it becomes more common with age (time for mutations to accumulate). It also explains why cancer therapies targeting single kinases often fail — resistant cells with additional mutations exist in the tumor and proliferate when the targeted cells die. Understanding the redundancy of checkpoint mechanisms is essential for understanding both cancer biology and cancer treatment.