Retinoblastoma and E2F Protein


Retinoblastoma and E2F Protein

  • Retinoblastoma is a human childhood disease, involving a tumor of the retina. 
  • It occurs both as a heritable trait and sporadically (by somatic mutation). 
  • It is often associated with deletions of band q 14 of human chromosome 13. 
  • The RB gene has been localized to this region by molecular cloning.

Summarizes the situation. 

  • Retinoblastoma arises when both copies of the RB gene are in-parental chromosome carries an alteration in this region. 
  • A somatic event in retinal cells that causes loss of the other copy of the RB gene causes a tumor. 
  • In the sporadic form of the disease, the parental chromosomes are normal, and both RB alleles are lost by (individual) somatic events.
  • The cause of retinoblastoma is therefore loss of protein function. 
  • Loss of RB is involved also in other forms of cancer, including osteosarcomas and small cell lung cancers.
  • RB is a nuclear phosphoprotein that influences the cell cycle. 
  • In resting (G0/G1) cells, RB is not phosphorylated. 
  • RB is phoshorylated during the cell cycle by cyclin/cdk complexes, most particularly at the end of G1; it is dephosphorylated during mitosis. 
  • The non-phosphorylated form of RB specifically binds several protein, and these interactions therefore occur only during part of the cell cycle (prior to S phase). 
  • Phosphorylation releases these protein.
  • The target proteins include the E2F group of transcription factors, which activate target genes whose products are essential for S phase. 
  • Binding to RB inhibits the ability of E2F to activate transcription, 
  • Which suggests that RB may repress the expression of genes dependent on E2F. 
  • In this way, RB indirectly prevents cells from entering S phase. 
  • Also, the RB-E2F complex directly represses some target genes, so its dissociation allows them to be expressed.
  • Certain viral tumor antigens bind specifically to the non-phosphorylated from of RB. 
  • The best characterized are SV40 T antigen and adenovirus E1A. 
  • This suggests the model shown in Non-phosphorylated RB prevents cell proliferation , this activity must be suppressed in order to pass through the cell cycle, which is accomplished by the cyclic-phosphorylation. 
  • And it may also be suppressed when a tumor antigen sequesters the non-phosphorylated bind E2F, the E2F is permanently free to allow entry into S phase (and the RB-E2F complex is not available to repress its target genes.)

Over-expression of RB impedes cell growth. 

  • An indication of the importance of RB for cell proliferation is given by the properties of an osteosarcoma cell line that lacks RB; 
  • when RB is introduced into this cell line, its growth is impeded. 
  • However, the inhibition can be overcome by expression of D cyclins, which form cdk-cyclin combinations that phosphorylate RB. RB is not the only proteins of its type : proteins with related sequences, called p107 and p130, have similar properties.
  • The connection between the cell cycle and tumor genesis is illustrated in several regulators are identified as tumor suppressors by the occurrence of inactivating mutations in tumors. 
  • In addition to RB itself, there are the small inhibitory proteins (most notably p16 and possibly p21), and D cyclin. 
  • Although these proteins (most notable RB) play a role in the cycle of a proliferating cell, the role that is relevant for tumor-genesis is more probably their function in the quiescent (G0) state. 
  • In quiescent cells, RB is not phosphorylated, 
  • D cyclin levels are low or absent, and p16, p21 p27 ensure inactivity of cdk-cyclin complexes, 
  • The loss of this circuit is necessary for unrestrained growth.
Print Friendly, PDF & Email

Leave a Reply