Molecular and Cellular Biochemistry

, Volume 286, Issue 1–2, pp 67–76 | Cite as

Xaf1 can cooperate with TNFα in the induction of apoptosis, independently of interaction with XIAP

  • Yan Xia
  • Rachel Novak
  • Jennifer Lewis
  • Colin S. Duckett
  • Andrew C. Phillips
Article

Abstract

XIAP-associated factor 1 (Xaf1) binds XIAP and re-localizes it to the nucleus, thus inhibiting XIAP activity and enhancing apoptosis [1]. Xaf1 expression is reduced or absent in tumor samples and cell lines suggesting it may function as a tumor suppressor [2–5]. To further study Xaf1 function we generated Xaf1 inducible cells in the osteosarcoma cell line Saos-2. Despite Xaf1 inducing apoptosis that is dramatically enhanced by TNFα we find no evidence for an interaction between Xaf1 and XIAP. Furthermore, Xaf1 expression sensitized XIAP−/− fibroblasts to TNFα, demonstrating the existence of a novel mechanism of Xaf1 induced apoptosis distinct from antagonizing XIAP. Xaf1 expression promotes cytochrome c release that cannot be blocked by inhibition of caspase activity. This implicates a role for the mitochondrial apoptotic pathway, consistent with the ability of Bcl2 to block Xaf1 induced apoptosis. The data indicate that in Saos2 cells Xaf1 activates the mitochondrial apoptotic pathway to facilitate cytochrome c release, thus amplifying apoptotic signals from death receptors.

Keywords

Xaf1 XIAP TNFα cytochrome c caspase Bcl2 tumor suppressor 

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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Yan Xia
    • 1
  • Rachel Novak
    • 1
  • Jennifer Lewis
    • 2
  • Colin S. Duckett
    • 2
  • Andrew C. Phillips
    • 1
  1. 1.Medical College of GeorgiaInstitute of Molecular Medicine and GeneticsAugustaUSA
  2. 2.University of Michigan, Departments of Pathology and Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA

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