Cell Cycle - Complete review
Q1. Which phase of cell cycle has most variability?
Ans = G1
G0 phase = Resting phase of stable parenchymal cells.
G2 phase: synthesis of tubulin for mitotic spindle.
G1/S Checkpoint = It is the most critical phase of the cell cycle.
There are two main cell cycle checkpoints one at the G1/S transition and the other at the G2/M transition
RB gene is called as Governor of Proliferation. RB, a key negative regulator of the G1/S cell cycle transition, is directly or indirectly inactivated in most human cancers.
DNA DAMAGE INDUCED CELL CYCLE ARREST CAN OCCUR AT THREE POINTS [Ref Devita 7ed/pg89]
 p53 dependent - G1/S arrest ( Acts mainly through p21 to cause cell cycle arrest.)
 p53 independent intra S phase checkpoint.www.pgmeeuploads.com
 p53 dependent [GADD 45] and p53 independent G2/M arrest. [ The primary mechanism underlying G2 DNA damage is p53 independent : Ref Devita 7ed/pg89]
So Major Role of p53 is G1/S arrest > G2/M arrest.
Q2. The tumor supressor gene p53 induces cell cycle arrest at :[ AIIMS 2005]
 G1-S check point
 G2-M check point
 S-G2 phase
 G0 phase
Ans =  Major Role of p53 is G1/S arrest > G2/M arrest.[ See above]
IMPORTANT POINTS FOR p53
 Guardian of the Genome.
 Role in both checkpoints = Major Role of p53 is G1/S arrest > G2/M arrest.
 At G1/S acts mainly through p21 to cause cell cycle arrest. www.pgmeeuploads.com
 Can induce apoptosis by activation proapoptotic genes as BAX
 MDM2 is negative feedback regulator of p53.
 Induce DNA repair by GADD45 and if fails can lead to GADD45 mediated G2/M arrest.
NOTE : p63 is essential for the differentiation of stratified squamous epithelia, while p73 has strong pro-apoptotic effects after DNA damage induced by chemotherapeutic agents.
Cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 regulate the G1-to-S transition by phosphorylating the Rb protein (pRb). [ Most important among these by oncogenes is point of view is Cyclin D-CDK4 = The current paradigm is that loss of normal cell cycle control is central to malignant transformation and that at least one of four key regulators of the cell cycle (p16/INK4a, cyclinD , CDK4, RB) is dysregulated in the vast majority of human Cancers] www.pgmeeuploads.com
Cyclin A-CDK2 and cyclin A-CDK1 are active in the S phase.
Cyclin B-CDK1 is essential for the G2-to-M transition.
Q3. Which CDK is thought to be mechanism of G2/M checkpoint genes?www.pgmeeuploads.com
Ans = CDK 1 levels control passage through G2 to M.
Q4. Transition from G2 to M phase of the cell cycle is controlled by [ AIIMS 2003]
 RB gene product
 Cyclin E
 Cyclin B
Ans = Cyclin B-CDK1 is essential for the G2-to-M transition. p53 is also involved in this transition However p53 independent mechanisms are more important. So here answer = Cyclin B >> p53.
ALL ABOUT CDK INHIBITORS
Two families of CDK inhibitors can block activity of CDKs and progression through the cell cycle.
 The so-called INK4 inhibitors, composed of p16, p15, p18, and p19, act on cyclin D-CDK4 and cyclin D-CDK6. [ ie INK 4 inhibitors mainly act at Regulators of G1/S checkpoint]
 The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs. [ Act throughout Cycle - Broad spectrum CDK inhibitors] NOTE : p21 is induced by the tumor suppressor p53 and it inhibits CDKs [ Mainly CDK2 ] to inhibit cell cycle at G1/S checkpoint.
Q5. Which of the following is not a CDK inhibitor:- [ AIIMS 2001]
Ans = p53 [ p53 do not directly inhibit CDK. It acts mainly through p21 to cause cell cycle arrest.
Q6. Which of the following play important role at G1/S transition [ Multiple response type] :- www.pgmeeuploads.com
 RB gene & p53 gene
 INK4 inhibitors.
Ans =  ,  ,  &  Only [Read above]
SOME MOST COMMONS
 Most common target for genetic alteration in human tumors is?
 Most common target for genetic alteration among tumor supressor gene is ? www.pgmeeuploads.com
 Most common target for genetic alteration among oncogenes is ?
 Most common target for genetic alteration among nuclear regulatory proteins/Transcription Factors is?
 Most common target for genetic alteration among cell cycle regulators is?www.pgmeeuploads.com
 Most common target for genetic alteration among CDK inhibitors in human tumors is ?
 Apoptotic pathway that is most frequently disabled in cancer ?
 Most frequently mutated oncogenic pathway in human neoplasms ?
 = p53
 = p53
 RAS = 90% of pancreatic adenocarcinomas and cholangiocarcinomas contain a RAS point mutation, as do about 50% of colon, endometrial, and thyroid cancers and about 30% of lung adenocarcinomas and myeloid leukemias.
NOTE = Most common mutation in Pancreatic adenocarcinoma is p16 (deleted in 95% of tumors).
NOTE = Most common oncogene mutation in Pancreatic adenocarcinoma is = KRAS
 = Intrinsic apoptotic pathway (mitochondrial pathway).
 = Receptor tyrosine kinase pathway.
RADIATION DAMGE TO CELL
MOST RADIOSENSITIVE =G2/M transition> (M > G2 phase) > G1 phase > Early S phase > End of S phase. [Ref : Principles and practice of radiation therapy by washington lever 2ed page 65] www.pgmeeuploads.com
Q7. Which of the following is most radiosensitive phase of cell cycle [ AIIMS 2002]
Ans =  M [ Note If G2/M transition is present in option than its the answer]
NOTE - Major cell death mechanisms involved in radiation therapy is Mitotic cell death or Mitotic catastrophe > Apoptosis [Note others are Necrosis and Autophagy] Following radiation, necrosis is seen less frequently but does occur in cancer cell lines or tissues.
NOTE : Chemotherapy induces both necrosis and apoptosis. [ Harrison 16ed/page 469]
Cell cycle specific Antineoplastic agents (CCS)
• Antimetabolites (cytarabine) 5-FU, 6.MP, MTX, 6-TG)
• Topoisomerase Poisons = Podophyllotoxins (Etoposide, Teniposide) are Topoisomerase II inhibitors whereas Campothecin is Topoisomerase I inhibitor.
• Mitotic spindle Inhibitors = Vinca alkaloids (Vinblastine & Vincristine), Taxanes (Paclitaxel & Docetaxil) & Estramustine.
Antimetabolites are S phase inhibitors.
Bleomycin cause cell cycle arrest in G2 phase.
Topoisomerase Poisons block cells in prominent G2 arrest > S phase.
Mitotic spindle inhibitor block cells in M phase.
Cell Cycle Non-specific (CCNS)
• Alkylating agent e.g. Busulfan, CPM, mechlorethamine, melfalan, thiotepa.
• Antibiotics -ACT-D, Daunorubicin, Doxorubicin, Plicamycin, Mitoxantrone.
• Nitrosoureas - BCNU, CCNU, M-CCNU