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Cell Cycle Regulator

  1. Normal cell cycle regulator
    1. CDK-I: drive cell cycle by phosphorylating critical target proteins Q
      i. Expressed constitutively during cell cycle, but in an inactive form
      ii. Activated by phosphorylation (after binding to cyclins)
    2. ​​Cyclins: Synthesized during specific phases of cell cycle
      1. Active CDKs
      2. Cyclin D,E,A,B appear sequentially during cell cycle
    3. Cycline D and Rb protein
  2. Cyclin D –
    I. First cyclin to appear (in G1 phase)
    1. Disappears in Sphase
    2. Three forms D1,D2,D3
    3. Degraded by ubiquitin -proteasome pathway Q
    4. Cyclin D activates CDK4
    5. Cyclin D-CDK4 complex promotes cell replication by phosphorylating Rb protein
II. Rb Protein:
Encoded by Rb gene (tumor suppressor gene) on 13q14. Q      
  1. Main barrier to cell cycle progression from G1-Sphase.
  2. Molecular ON-OFF switch, applies breaks to cell cycle.
  3. Active form of Rb-Hypophosphorylated Rb. Found in Quiescent cells.
  4. Binds E2F site and inhibits DNA transcription
  5. E2F/Rb complex recruits histone deacetylase → compaction of nuclear chromatin and   inhibition of DNA transcription.
  6. When Quiescent cells are stimulated by growth factors → cyclin D/CDK4 complex phosphorylates Rb protein Hyper phosphorylated Rb dissociates from E2F factors → Activation of transcription of E2F target genes-→ progression through Sphase
Cyclin E/CDK2
  1. G1/S transition and progression through Sphase
Cyclin A/CDK2       
  1. Initiates G2M transition
  2. Regulation of events at mitotic prophase
Cyclin B/CDK1 - Activated by protein phosphatase
  1. G2M transition
  2. Progression beyond prophase
  3. Regulates critical events at G2M transition
Cell Cycle Inhibitors
  1. Activity of cyclins/CDKs regulated by inhibitors
  2. Function as tumor suppressor genes.
  3. Two families 

1. CIP/WAF family: p21. p27. p57

  1. Block the cell cycle by binding to cyclins/CDK complex
  2. P21 is induced by p53
  3. P27 is induced by growth suppressors like TGF

2. INK4/ARF family: p16 INK4A, p14 ARF Q      

  1. P16INK4A-Binds cyclin D/CDK4 complex and promotes inhibitory effects of Rb
  2. P14ARF- p53 level by inhibiting MDM2 activity (MDM2 degrades p53) 

3. Cell cycle checkpoints: Two check points in cell cycle

  1. G1 S check point Q : Looks for DNA damage before DNA replication
  2. G2 M check pointQ: Damaged DNA can be repaired even after its replication provided sister chromatids have    not separated. G2 M check point is important in cells exposed to ionizing radiation. Defects in G2 M will give rise to chromosomal abnormalities.

Important check point for cell exposed to radiation


Fig: Role of cyclins, CDKs, and CDKIs in regulating the cell cycle


4. Sensor of DNA damage at these check points

  1. RAD family Q
  2. Ataxia telangiectasia mutated (ATM) Q
    1. ATM- activated by mechanisms that cause double standard DNA breaks, send signals to arrest cell cycle.
    2. G1S check point Act through p53  
    3. G2M check point-Act both through p53 dependent mechanism and through inactivation of cdc 25 phosphatases (disrupt cyclin B/CDK1). Component of network genes include BRCA1 and BRCA2 Q 

5. Activation of Oncogenes:

Structural abnormality of gene → abnormal gene product (onco protein)

Aberration in regulation => inappropriate production of structurally (n) protein

  1. Point mutation: eg. Ras
  2. Chromosomal rearrangement:
    1. Translocation                       
    2. Inversion 

6. Translocation:


a. Over expression -

  1. of p-onc by placing them under regulatory element of immunoglobulin or T cell receptor loci    e.g.  (8,14) in Burkitt's lymphoma)
  2. Mantle cell lymphoma t(11;14): chromosome (14 IgH locus; chromosome 11-bcl-1 locus) Follicular lymphoma (14;18) chromosome (18--+bcl z locus; chromosome 14-IgH locus) 

b. Translocation –

+ recombination of two loci --+ formation of hybrid gene --+ chimeric gene product e.g. Ph   chromosome


c. In Ewing's sarcoma:

  1. T(11;12) : - EWS gene at chromosome 22, 
  2. FL-I--+ gene at chromosome 11
  3. Chimeric EWS-FL-I--+ trans activator of c-myc promoter 

d. Gene Amplification: Q ­

  1. Detected by molecular hybridization with appropriate DNA probe Two patterns
  2. dms - double minutes - small, chromosome like structures
  3. HSRs - homogenous staining regions


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