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cIAP1, cIAP2, and XIAP act cooperatively via nonredundant pathways to regulate genotoxic stress-induced nuclear

Hyung-Seung Jin1, Dong-Hee Lee, Dong-Hwan Kim

  • 1Department of Biology, College of Life Science and Biotechnology and Protein Network Research Center, Yonsei University, Seoul, Republic of Korea.

Cancer Research
|February 19, 2009
PubMed

Insights

Inhibitors of apoptosis proteins (IAPs) are crucial for genotoxic stress-induced nuclear factor-kappaB (NF-kappaB) activation. Specific IAPs like XIAP and cIAP1 mediate key steps, including NEMO ubiquitination, essential for NF-kappaB pathway signaling.

Area of Science:

  • Cellular signaling pathways
  • Molecular mechanisms of DNA damage response
  • Ubiquitin-protein ligase activity

Background:

  • Genotoxic agents trigger nuclear monoubiquitination of NEMO/IKKgamma, a key regulator of the IKK complex.
  • NEMO ubiquitination is essential for the activation of the IkappaB kinase (IKK) complex and subsequent nuclear factor-kappaB (NF-kappaB) signaling.
  • The specific E3 ligase responsible for NEMO ubiquitination and the precise mechanism of IKK activation remain unidentified.

Purpose of the Study:

  • To elucidate the role of Inhibitors of Apoptosis Proteins (IAPs) in regulating genotoxic stress-induced NF-kappaB activation.
  • To identify the specific IAPs involved in NEMO ubiquitination and IKK activation.
  • To understand the nonredundant functions of IAPs in the NF-kappaB pathway beyond their known anti-apoptotic roles.

Main Methods:

  • Investigated the involvement of IAPs in NF-kappaB activation using genotoxic agents like camptothecin, etoposide/VP16, and doxorubicin.
  • Utilized biochemical assays to determine the roles of XIAP, cIAP1, and cIAP2 in specific steps of the NF-kappaB signaling cascade.
  • Examined the interaction between IAPs, TAK1, IKK complex, and NEMO ubiquitination.

Main Results:

  • XIAP mediates the activation of TAK1 and its coupling to the IKK complex in response to camptothecin or etoposide/VP16.
  • XIAP is not required for doxorubicin-induced NF-kappaB activation, which involves a MEK-ERK pathway.
  • cIAP1 was identified as the E3 ligase responsible for NEMO ubiquitination, while cIAP2 regulates a downstream event.
  • IAPs exhibit nonredundant, cooperative roles in activating NF-kappaB in response to genotoxic stress.

Conclusions:

  • Inhibitors of Apoptosis Proteins (IAPs) play multifaceted roles in genotoxic stress-induced NF-kappaB activation.
  • Specific IAPs, including XIAP, cIAP1, and cIAP2, contribute nonredundantly to distinct steps of the NF-kappaB signaling pathway.
  • This study reveals novel functions of IAPs in DNA damage response, extending beyond their canonical caspase inhibitory activities.

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