Activation of APC by TGF-beta Suppresses Breast Cancer

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DESCRIPTION (provided by applicant): Loss of TGF-beta growth inhibition is a hallmark of many human tumors. The TGF-beta signaling pathway involves the activation of anaphase-promoting complex (APC), a multisubunit ubiquitin protein ligase, which in turn facilitates the destruction of SnoN, a transcriptional co-suppressor, thereby mediating the transactivation of TGF-beta responsive genes responsible for cell cycle arrest. APC appears to act in conjunction with other moieties, including Cdh1 and Smad2/Smad3, but the mechanism by which it is activated by TGF-beta signaling is poorly understood. The objectives of the current proposal are to elucidate that mechanism and further validate the role of TGF-beta activated APC in suppressing tumor formation using human, breast tumor xenografts in a mouse model. We have recently obtained evidence implicating the phosphorylation of Cdc27, a key subunit of APC, in the process of activation, as well as evidence suggesting that the responsible enzyme may be casein kinase II. Based on these and other data, we hypothesize that TGF-beta activates APC through a process that involves Cdc27 phosphorylation and Smad2/Smad3 recruitment of Cdh1. Our specific aims will be (1) to identify the kinase responsible for phosphorylation of Cdc27 by confirming the role of casein kinase II and/or determining a role for other candidate kinases; (2) to characterize the nature of the interactions between the kinase and APC and their biological consequences (SnoN destruction and cell cycle arrest); and (3) to validate the role of activation of APC by TGFbeta in suppressing tumor progression in a human, breast tumor xenograft mouse model. Understanding the biological mechanisms involved in TGF-beta signaling via APC and validating the role of APC as a TGF-beta effecter in the inhibition of breast tumor progression will be important for future studies that seek to determine how impaired signaling contributes to oncogenesis and for identification of potential targets for therapeutic intervention.