Retinoblastoma protein

Overview
The retinoblastoma protein, also called pRb or Rb, is a tumor suppressor protein found to be dysfunctional in a number of types of cancer. pRb was so named because retinoblastoma cancer results when the protein is inactivated by a mutation in both alleles of the RB1 gene that codes for it. The "p" in pRb stands for protein and is a way to distinguish it from the gene, Rb. pRb is usually present as a phosphoprotein inside cells and is a target for phosphorylation by several kinases as described below. One highly studied function of pRb is to prevent the cell from dividing or progressing through the cell cycle. Thus, when pRb is ineffective at this role, mutated cells can continue to divide and may become cancerous.

pRb is a member of the 'Pocket protein family', because it has a pocket to which proteins can bind. Oncogenic proteins such as those produced by cells infected by high-risk types of human papillomaviruses can bind and inactivate pRb, which can lead to cancer.

Cell cycle suppression
pRb prevents the cell from replicating damaged DNA by preventing its progression through the cell cycle into its S, or synthesis phase or progressing through G1, or first gap phase. pRb binds and inhibits transcription factors of the E2F family. E2F transcription factors are dimers of an E2F protein and a DP protein. The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase. As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When pRb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle. The pRb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, further suppressing DNA synthesis.

Activation and inactivation
pRb can actively inhibit cell cycle progression when it is dephosphorylated while this function is inactivated when pRb is phosphorylated. pRb is activated near the end of G1 phase when a phosphatase dephosphorylates it, allowing it to bind E2F.

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate pRb, inhibiting its activity. The initial phosphorylation is performed by Cyclin D/CDK4,6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.

Phosphorylation of pRb allows E2F-DP to dissociate from pRb and become active. When E2F is freed it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.