• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.

Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.

Pubmed ID: 18022362

Authors

  • Varfolomeev E
  • Blankenship JW
  • Wayson SM
  • Fedorova AV
  • Kayagaki N
  • Garg P
  • Zobel K
  • Dynek JN
  • Elliott LO
  • Wallweber HJ
  • Flygare JA
  • Fairbrother WJ
  • Deshayes K
  • Dixit VM
  • Vucic D

Journal

Cell

Publication Data

November 16, 2007

Associated Grants

None

Mesh Terms

  • Animals
  • Apoptosis
  • Cell Line
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Molecular Structure
  • NF-kappa B
  • Neoplasms
  • Polyubiquitin
  • Proteasome Endopeptidase Complex
  • Protein Structure, Tertiary
  • Signal Transduction
  • Tumor Necrosis Factor-alpha
  • Ubiquitination