Retinoblastoma Protein (pRb)
The retinoblastoma protein, also known as pRb or p105, is a tumour suppressor protein, and is one of many proteins that has an important role in the regulation of the cell cycle. The Rb protein was first discovered in 1986 through studies of an inheritable children's eye cancer called retinoblastoma, as its name suggests, which was found to have a lack of retinoblastoma gene (Rb or Rb1), the gene which encodes pRb. This loss of the Rb gene and hence loss of the Rb protein within retinoblastoma proposed pRb had functional qualities associated with the inhibition of growth and division of cells, and this hallmark initiated research into the retinoblastoma protein.
The main function of pRb is the inhibition of the cell cycle at the restriction point at the late G1 phase, temporarily preventing the cells progression into the S phase. Towards the end of G1 phase, pRb, as well as two related proteins p107 and p130, bind and inhibit transcriptional factors of E2F, a gene regulatory protein, blocking the pathway of DNA transcription required for S phase entry[4,6]. This is known as the restriction point of the cell cycle. Here pRb specifically interacts with histone deacetylase complexes of the E2F family, becomes active and is hypophosphorylated[6,7].
pRb becomes inactive when it is phosphorylated by protein cyclin-dependent kinases Cdk4 and Cdk6 in mid G1 phase, and Cdk2 in late G1 phase, reducing its attraction to E2F, and thus unblocking and allowing the cell to pass the restriction point in order to progress from the G1 phase into the S phase of the cell cycle[Purves,6]. This dissociation of pRb from E2F allows E2F to carry out its usual functional role in the activation of S phase gene expression. Prior to this crutial step pRb phosphorylation, the activation of three different types of Cdks must occur through the synthesis and binding of cyclin D to Cdk4 and Cdk6, and cyclin E to Cdk2, which form cyclin-cdk complexes Cdk4-cyclin D, Cdk6-cyclin D and Cdk2-cyclin E, respectively[Purves,6]. This intracellular cascade is activated by extracellular signals which stimulate the initial phosphrylation of pRb.
Importance of pRb
1. The retinoblastoma protein--from bench to bedside.
2. Purves et al. Life The Science Of Biology 7E
4. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=retinoblastoma protein&rid=mboc4.section.3214#3232
5. The family of retinoblastoma proteins.
6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=retinoblastoma protein&rid=mcb.section.3553#3560 MCB1