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From CellBiology

Retinoblastoma Protein (pRb)

The retinoblastoma protein, also known as pRb or p105[5], 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[1] through studies of an inheritable childrens 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[3]. 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[4].


Function

phosphorylation of pRb leads to disassociation of E2F and activation of transcription [7]

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[4]. 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[4].

The retinoblastoma protein is maintained in a phophorylated state throughout phases S, G2 and M (see Cell Division) of the cell cycle. After mitosis is completed cdk-cyclin levels drop and lead to the dephophorylation of pRb, and as a results hypophophorylated pRb is formed ready for reuse in the early stages of G1.

Importance of pRb

The retinoblastoma protein is a very important regulatory protein within the cell cycle, as it is a tumour suppressor protein. If loss of function of pRb occurs and pRb cannot carry out its inhibitory role at the restriction point, this can have detrimental effects, including the uncontrolled division of cells leading to cancerous growth. An example of this can be seen in the Human papillomavirus (HPV) where the function of Rb protein and p53, another tumour suppressive protein, can contribute to the progression of cervical cancer[8].

References

1. Mittnacht S 2005, 'The retinoblastoma protein--from bench to bedside', European Journal of Cell Biology, 84(2-3):97-107

2. Purves W K, Sadava D, Orians G H & Heller H C, 2004, Life The Science Of Biology, 7th Edn, Sinauer Associates Inc.

3. http://www.nature.com/celldivision/milestones/full/milestone15.html

4. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=retinoblastomaprotein&rid=mboc4.section.3214#3232

5. Stiegler P & Giordano A, 2001, 'The family of retinoblastoma proteins', Critical Reviews In Eukaryotic Gene Expression, 11(1-3):59-76

6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=retinoblastomaprotein&rid=mcb.section.3553#3560

7. http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=2009_Lecture_15

8. Subramanya D & Grivas PD, 2008, 'HPV and cervical cancer: updates on an established relationship', Postgraduate Medicine, 120(4):7-13