Survivin Monomer Plays an Essential Role in Apoptosis Regulation

Marat S Pavlyukov,Nadezhda V Antipova,Maria V Balashova,Tatjana V Vinogradova,Evgenij P Kopantzev,Mihail I Shakhparonov

doi:10.1074/jbc.m111.237586

Marat S Pavlyukov, Nadezhda V Antipova + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m111.237586

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Abstract

Survivin was initially described as an inhibitor of apoptosis and attracted growing attention as one of the most tumor-specific genes in the human genome and a promising target for cancer therapy. Lately, it has been shown that survivin is a multifunctional protein that takes part in several crucial cell processes. At first, it was supposed that survivin functions only as a homodimer, but now data indicate that many processes require monomeric survivin. Moreover, recent studies reveal a special mechanism regulating the balance between monomeric and dimeric forms of the protein. In this paper we studied the mutant form of survivin that was unable to dimerize and investigated its role in apoptosis. We showed that survivin monomer interacts with Smac/DIABLO and X-linked inhibitor of apoptosis protein (XIAP) both in vitro and in vivo. Due to this feature, it protects cells from caspase-dependent apoptosis even more efficiently than the wild-type survivin. We also identified that mutant monomeric survivin prevents apoptosis-inducing factor release from the mitochondrial intermembrane space, protecting human fibrosarcoma HT1080 cells from caspase-independent apoptosis. On the other hand, our results indicate that only wild-type survivin, but not the monomer mutant form, enhances tubulin stability in cells. These findings suggest that survivin partly performs its functions as a monomer and partly as a dimer. The mechanism of dimer-monomer balance regulation may also work as a "switcher" between survivin functions and thereby explain remarkable functional diversities of this protein.

Highlights

The results (Fig. 2D) give evidence that the survivin dimerization region is essential for interactions with Smac/DIABLO, but without the baculoviral IAP repeat (BIR) domain it was not able to bind this protein
Schools, a grant from the Basic Research Program (Physico-Chemical Biology) of the presidium of Russian Academy of Science, Federal Program of the Department of Education and Science of Russian Federation Grant 2007-02-2.2-05-01-006, Russian Foundation for Basic Research, and by the Fund for Assistance to Innovative Enterprises (FASIE). □S The on-line version of this article contains supplemental materials, Fig. S1, and additional references. 1 To whom correspondence should be addressed: Ul, Marshala Timoshenko 36, Moscow 121359, Russia
We showed that a survivin mutant unable to dimerize can interact with Smac/DIABLO both in vivo and in vitro, before our study it was considered to be impossible [17, 18]

Summary

Introduction

The results (Fig. 2D) give evidence that the survivin dimerization region is essential for interactions with Smac/DIABLO, but without the BIR domain it was not able to bind this protein. SurvivinF101A/L102A Protects Fibrosarcoma Human Cells HT1080 from Caspase-dependent Apoptosis More Effectively Than WT Survivin—To investigate the role of survivin monomer in apoptosis regulation we constructed cell lines HT1080 stably expressing WT survivin or one of the following survivin mutant forms: survivinF101A/L102A, survivinD53A, or survivinD53A/F101A/L102A, all containing N-terminal CFP.

Results

Conclusion