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.