APC/C and retinoblastoma interaction: cross-talk of retinoblastoma protein with the ubiquitin proteasome pathway.

Ajeena Ramanujan,Swati Tiwari

doi:10.1042/bsr20160152

Ajeena Ramanujan, Swati Tiwari

Open Access

https://doi.org/10.1042/bsr20160152

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Journal: Bioscience reports	Publication Date: Sep 16, 2016
Citations: 13	License type: CC BY 4.0

Affiliation: Jawaharlal Nehru University

Abstract

The ubiquitin (Ub) ligase anaphase promoting complex/cyclosome (APC/C) and the tumour suppressor retinoblastoma protein (pRB) play key roles in cell cycle regulation. APC/C is a critical regulator of mitosis and G1-phase of the cell cycle whereas pRB keeps a check on proliferation by inhibiting transition to the S-phase. APC/C and pRB interact with each other via the co-activator of APC/C, FZR1, providing an alternative pathway of regulation of G1 to S transition by pRB using a post-translational mechanism. Both pRB and FZR1 have complex roles and are implicated not only in regulation of cell proliferation but also in differentiation, quiescence, apoptosis, maintenance of chromosomal integrity and metabolism. Both are also targeted by transforming viruses. We discuss recent advances in our understanding of the involvement of APC/C and pRB in cell cycle based decisions and how these insights will be useful for development of anti-cancer and anti-viral drugs.

Highlights

Somatic cell cycle has alternating DNA synthetic (S) and mitotic (M) phases, separated by gap phases (G1 and G2)
We review the recent advances in our understanding of how anaphase promoting complex/cyclosome (APC/C) regulates G0/G1 stage and controls S-phase entry and discuss the implications of its interaction with the tumour suppressor protein retinoblastoma for cell cycle regulation and development of anti-viral and anti-cancer drugs
The protein retinoblastoma (pRB)–E2F complex is transferred from SV40LT to the ATPase domain of hsc70 resulting in ATP hydrolysis and conformational changes in hsc70 thereby releasing pRB and E2F as separate molecules (Figure 3B) [85]. These results suggest that pRB associates with viral oncoproteins and E2F through overlapping but distinct domains and viral LxCxE is necessary for its binding to pRB, though not sufficient to displace E2F

Summary

Introduction

Somatic cell cycle has alternating DNA synthetic (S) and mitotic (M) phases, separated by gap phases (G1 and G2). E7 protein carrying mutations outside the LxCxE motif inhibits RB-E2F binding, but retains cell cycle arrest [87], demonstrating that LxCxE dependent interactions of pRB to be distinct from pRB pool binding to E2Fs. These studies indicate that E2F independent pRB pathways guard proliferative pathways.

Results

Conclusion