RB depletion is required for the continuous growth of tumors initiated by loss of RB.

Alex Doan,David M Feldser,Hannes Vogel,Myung Chang Lee,Andrea C Chaikovsky,Shuyuan Zhang,Julien Sage,Lukas E Dow,Diana Gong,Jan M Skotheim,Julia Arand,Alexandros P Drainas,Yan Ting Shue,David M Walter,Bruce E Clurman

doi:10.1371/journal.pgen.1009941

Abstract

The retinoblastoma (RB) tumor suppressor is functionally inactivated in a wide range of human tumors where this inactivation promotes tumorigenesis in part by allowing uncontrolled proliferation. RB has been extensively studied, but its mechanisms of action in normal and cancer cells remain only partly understood. Here, we describe a new mouse model to investigate the consequences of RB depletion and its re-activation in vivo. In these mice, induction of shRNA molecules targeting RB for knock-down results in the development of phenotypes similar to Rb knock-out mice, including the development of pituitary and thyroid tumors. Re-expression of RB leads to cell cycle arrest in cancer cells and repression of transcriptional programs driven by E2F activity. Thus, continuous RB loss is required for the maintenance of tumor phenotypes initiated by loss of RB, and this new mouse model will provide a new platform to investigate RB function in vivo.

Highlights

Tumors arise from normal cells upon an accumulation of alterations, including genetic and epigenetic loss-of-function events affecting tumor suppressor genes and gain-of-function events affecting oncogenes
Functional inactivation of retinoblastoma tumor suppressor protein (RB) leads to unchecked proliferation and is a frequent occurrence in human cancer
The mechanisms through which RB carries out its tumor suppressor function remain only partly understood

Summary

Introduction

Tumors arise from normal cells upon an accumulation of alterations, including genetic and epigenetic loss-of-function events affecting tumor suppressor genes and gain-of-function events affecting oncogenes. Frequent alterations in many cancer types are found in members of the so-called “RB pathway”, and this pathway has been serving as a paradigm in cancer research for several decades. In this pathway, the retinoblastoma tumor suppressor protein (RB) controls the activity of the E2F family of transcription factors, which are themselves implicated in the transcription of genes whose products are important for cell cycle progression, especially at the G1/S transition of the cell cycle. RB is found to be frequently inactive, either because of direct genetic and epigenetic inactivation of the RB gene ( known as RB1) but more frequently by alterations that result in increased activity of the RB kinases Cyclin D-CDK4/6 and Cyclin E-CDK2 (reviewed in [3,4,5,6])

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Conclusion