ROLE OF KAISO IN METASTASIS

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DESCRIPTION (Adapt from applicant's abstract): Disturbances in E-cadherin cell adhesion are known to contribute to tumor progression. E-cadherin is down regulated or lost altogether in about 50% of highly metastatic carcinomas. The PI has identified a novel POZ/ZF transcription factor Kaiso that associates with catenin p120. He suggests that this protein complex may be involved in a signal pathway analogous to that associated with b-catenin-Lef1/TCF that figures prominently in the progression of melanoma and colon carcinoma. POZ/ZF proteins in general appear to be involved in numerous human cancers. The preliminary data of the PI indicates that p120 mislocalizes to the cytoplasm and nucleus in E-cadherin deficient carcinomas. Thus p120 may be intrinsically active as a signaling molecule when not bound to E-cadherin. Moreover, putative Kaiso target genes have been identified that are responsive to the presence or absence of E-cadherin and have roles promoting migration and invasiveness. The PI wishes to test a hypothesis that in E-cadherin deficient cells, p120 trans-activates Kaiso leading to transcription of target genes involved in metastasis. In Aim 1 the PI will define the role of Kaiso and p120 in transcription using artificial promotor/reporters containing an affinity Kaiso DNA binding site. In aim 2 additional Kaiso target genes will be identified by microarray technology. The PI contends that identification of novel Kaiso target genes should provide clues to the role of Kaiso and should reveal new genes and their promotors that will be used to elucidate signaling pathways upstream of Kaiso. In aim 3 he describes strategies to 1) elucidate the role of p120 and Kaiso in regulating transcription of a model downstream Kaiso target gene and 2) relate the findings to the biology of metastasis. Thus natural promotor/reporter constructs that reflect the regulation of the target will be used to elucidate upstream signaling pathways. The pathways will then be reevaluated in the context of well-defined breast cancer model systems to relate these findings directly to mechanisms promoting cell motility, invasion and metastasis. The proposed experiments are expected to illuminate a largely unexplored area of cadherin biology, one that may have important implications for understanding metastasis.