Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma
Uma M. Sachdeva, Joan M. O’Brien
Uma M. Sachdeva, Joan M. O’Brien
Published February 1, 2012
Citation Information: J Clin Invest. 2012;122(2):425-434. https://doi.org/10.1172/JCI57114.
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Science in Medicine

Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma

Abstract

Retinoblastoma is a pediatric retinal tumor initiated by biallelic inactivation of the retinoblastoma gene (RB1). RB1 was the first identified tumor suppressor gene and has defined roles in the regulation of cell cycle progression, DNA replication, and terminal differentiation. However, despite the abundance of work demonstrating the molecular function and identifying binding partners of pRb, the challenge facing molecular biologists and clinical oncologists is how to integrate this vast body of molecular knowledge into the development of targeted therapies for treatment of retinoblastoma. We propose that a more thorough genetic understanding of retinoblastoma would inform targeted treatment decisions and could improve outcomes and quality of life in children affected by this disease.

Authors

Uma M. Sachdeva, Joan M. O’Brien

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Figure 3

The Skp2/p27/pRb pathway in the regulation of cell cycle progression.

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The Skp2/p27/pRb pathway in the regulation of cell cycle progression. (A...
(A) In response to proliferative signals, cellular levels of Skp2 increase, resulting in Skp2 binding to p27 and targeting it for degradation. This degradation of p27 relieves p27-mediated inhibition of the cyclin E–CDK2 complex during late G1, allowing for phosphorylation and inactivation of pRb and promoting G1 progression to S phase. (B) In the absence of proliferative signals, pRb is hypophosphorylated and binds to Skp2, preventing it from binding to p27. Skp2 is then complexed with APC/CCdh1 and is targeted for proteasomal degradation. Free p27 is then able to bind cyclin E–CDK2 and inhibit its activity, resulting in continued pRb activity and G1 cell cycle arrest.