Context dependent roles for RB-E2F transcriptional regulation in tumor suppression.

Michael J Thwaites,Matthew J Cecchini,Komila Zakirova,Frederick A Dick,Daniel T Passos,Srikumar Chellappan

doi:10.1371/journal.pone.0203577

Michael J Thwaites, Matthew J Cecchini + Show 4 more

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https://doi.org/10.1371/journal.pone.0203577

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Abstract

RB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.

Highlights

The maintenance of cell cycle control is crucial to the normal development and homeostasis of multicellular organisms [1]
Cell cycle exit in response to stimuli such as DNA damage is normal in Rb1G/G cells suggesting the effects of compromised RB-E2F transcriptional control are dependent on the context of the cell cycle decision
We aimed to investigate the role of RB-E2F transcriptional control in isolation from other RB family E2F regulation using cancer susceptibility of Rb1G/G mice as a simple read out

Summary

Introduction

The maintenance of cell cycle control is crucial to the normal development and homeostasis of multicellular organisms [1]. Misregulation of the cell cycle is widespread in tumorigenesis [2]. At the core of G1-S regulation are Cyclin dependent kinases (CDKs) and the Retinoblastoma (RB) family of proteins. Proliferative signals generally activate Ras and lead to Cyclin D-CDK4 or 6 upregulation, phosphorylation of RB, and the release of activator E2F transcription factors to induce cell cycle entry [4]. This is complemented by CDK phosphorylation of the RB family protein p130 that disassembles the DREAM transcriptional repressor complex, further contributing to E2F activation in early G1 [5]. Cyclin E-CDK2 is negatively regulated by the CDK inhibitor protein p27 in late G1

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