The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis

F. Chu, A. Borthakur, X. Sun, J. Barkinge, R. Gudi, S. Hawkins, Kanteti V.S. Prasad

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The human Siva gene is localized to chromosome 14q32-33 and gives rise to the full-length predominant form, Siva-1 and a minor alternate form, Siva-2 that appears to lack the proapoptotic properties of Siva-1. Our recent work has shown that the missing region in Siva-2 encodes a unique twenty amino acid putative amphipathic helical region (SAH, residues 36-55 in Siva-1). Despite the fact that Siva-1 does not belong to the BCL-2 family, it specifically interacts with the anti-apoptotic protein BCL-XL and sensitizes MCF7 breast cancer cells expressing BCL-XL to UV radiation induced apoptosis. Deletion mutagenesis has mapped the necessary region to the SAH in Siva-1. In this paper we demonstrate that the SAH region in Siva-1 is sufficient to specifically interact with the anti-apoptotic members of the BCL2 family such as BCL-XL and BCL-2 but not its apoptotic member BAX. Using transient transfections and direct microinjection of synthetic SAH peptides, we also demonstrate that the SAH region is sufficient to inhibit the BCL-XL mediated cell survival and render MDA-MB-231 and MCF7 breast cancer cells expressing BCL-XL highly susceptible to UV radiation induced apoptosis. The underlying mechanism of action of SAH mediated inhibition of BCL-XL (and/or BCL2) cell survival appears to be due to loss of mitochondrial integrity as reflected in enhanced cytochrome c release leading to the activation of caspase 9 and finally caspase 3.

Original languageEnglish (US)
Pages (from-to)83-95
Number of pages13
JournalApoptosis
Volume9
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

Keywords

  • Apoptosis
  • BAX
  • BCL-XL
  • BCL2
  • Caspase 3
  • Caspase 9
  • Cytochrome c
  • Siva
  • Siva-1
  • TNFR

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Fingerprint

Dive into the research topics of 'The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis'. Together they form a unique fingerprint.

Cite this