This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.IkappaB kinase alpha(IKKalpha) plays important but diverse roles in cancer development and progression. Nuclear IKKalpha functions as a tumor suppressor in Squamous Cell Carcinoma (SCC), but promotes tumor metastasis in prostate cancer (CaP). In both cancer types, IKKalpha nuclear translocation is essential for its cancer-related function. However, the mechanisms regulating IKKalpha nuclear translocation remain unknown. Recently, we have found that Transforming Growth Factor beta (TGFbeta) triggers IKKalpha nuclear translocation in keratinocytes and Myc-CaP cells, suggesting the cross-talk between TGFbeta and IKKalpha signaling. To investigate the mechanisms regulating IKKalpha nuclear translocation and its relevance in cancer development and progression, I will pursue the following:
Aim 1, Identify the cytoplasmic or nucleoplasmic retention factors for IKKalpha, with a particular emphasis on the role of Smad3 in TGFbeta mediated IKKalpha nuclear translocation.
Aim 2, Identify the critical domains and motifs for IKKalpha nuclear translocation.
Aim 3, Define the role of posttranslational modifications in IKKalpha nuclear-cytoplasmic shuttling.
Aim 4, Investigate the relevance of IKKalpha nuclear translocation in SCC development and progression. The accomplishment of this project will shed light on how IKKalpha signaling into the nucleus is regulated and contribute to the development of novel therapeutics for the treatment of human cancers.
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