Separation of Anti-proliferation and Anti-apoptotic Functions of Retinoblastoma Protein Through Targeted Mutations of Its A/B Domain

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2006 Dec 22

PMID 17183714

Citations 15

Authors

B Nelson Chau

Chris W Pan

Jean Y J Wang

Affiliations

Soon will be listed here.

Abstract

Background: The human retinoblastoma susceptibility gene encodes a nuclear phosphoprotein RB, which is a negative regulator of cell proliferation. The growth suppression function of RB requires an evolutionarily conserved A/B domain that contains two distinct peptide-binding pockets. At the A/B interface is a binding site for the C-terminal trans-activation domain of E2F. Within the B-domain is a binding site for proteins containing the LxCxE peptide motif.

Methodology/principle Findings: Based on the crystal structure of the A/B domain, we have constructed an RB-K530A/N757F (KN) mutant to disrupt the E2F- and LxCxE-binding pockets. The RB-K530A (K) mutant is sufficient to inactivate the E2F-binding pocket, whereas the RB-N757F (N) mutant is sufficient to inactivate the LxCxE-binding pocket. Each single mutant inhibits cell proliferation, but the RB-KN double mutant is defective in growth suppression. Nevertheless, the RB-KN mutant is capable of reducing etoposide-induced apoptosis.

Conclusion/significance: Previous studies have established that RB-dependent G1-arrest can confer resistance to DNA damage-induced apoptosis. Results from this study demonstrate that RB can also inhibit apoptosis independent of growth suppression.

Citing Articles

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Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies.

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Next-generation sequencing-based method shows increased mutation detection sensitivity in an Indian retinoblastoma cohort.

Singh J, Mishra A, Pandian A, Mallipatna A, Khetan V, Sripriya S Mol Vis. 2016; 22:1036-47.

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RB1 dual role in proliferation and apoptosis: cell fate control and implications for cancer therapy.

Indovina P, Pentimalli F, Casini N, Vocca I, Giordano A Oncotarget. 2015; 6(20):17873-90.

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A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice.

Cecchini M, Thwaites M, Talluri S, MacDonald J, Passos D, Chong J Mol Cell Biol. 2014; 34(11):2029-45.

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