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X-linked inhibitor of apoptosis protein functions as a cofactor in transforming growth factor-beta signaling
S Birkey Reffey1, J U Wurthner, W T Parks
1Metabolism Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of apoptotic cell death, which functions by directly inhibiting caspases, the principal effectors of apoptosis. Here we report that XIAP can also function as a cofactor in the regulation of gene expression by transforming growth factor-beta (TGF-beta). XIAP, but not the related proteins c-IAP1 or c-IAP2, associated with several members of the type I class of the TGF-beta receptor superfamily and potentiated TGF-beta-induced signaling. Although XIAP-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B was found to require the TGF-beta signaling intermediate Smad4, the ability of XIAP to suppress apoptosis was found to be Smad4-independent. These data implicate a role for XIAP in TGF-beta-mediated signaling that is distinct from its anti-apoptotic functions.
Insights
X-linked inhibitor of apoptosis protein (XIAP) regulates gene expression via transforming growth factor-beta (TGF-beta) signaling. This function is separate from its known role in suppressing apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- X-linked inhibitor of apoptosis protein (XIAP) is a key regulator of apoptosis by inhibiting caspases.
- Transforming growth factor-beta (TGF-beta) signaling pathways are crucial for various cellular processes, including gene expression and apoptosis.
Purpose of the Study:
- To investigate the potential role of XIAP as a cofactor in TGF-beta-mediated gene expression regulation.
- To differentiate XIAP's functions in TGF-beta signaling from its established anti-apoptotic activities.
Main Methods:
- Co-immunoprecipitation assays to detect XIAP association with TGF-beta receptors.
- Analysis of TGF-beta-induced signaling pathways (e.g., JNK, NF-kappa B) in the presence of XIAP.
- Assessment of Smad4-dependent and -independent mechanisms in XIAP's functions.
Main Results:
- XIAP, unlike c-IAP1/c-IAP2, associates with type I TGF-beta receptors.
- XIAP potentiates TGF-beta-induced signaling, activating JNK and NF-kappa B pathways in a Smad4-dependent manner.
- XIAP's anti-apoptotic function is independent of Smad4.
Conclusions:
- XIAP plays a novel role as a cofactor in TGF-beta-mediated gene expression.
- This TGF-beta signaling role of XIAP is distinct from its previously characterized anti-apoptotic functions.
- XIAP's involvement in TGF-beta signaling highlights its multifaceted cellular regulatory capabilities.