TGF-β activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth.

摘要: We previously reported that aberrant TGF-β/Smad2/3 signaling in endometrial cancer (ECA) leads to continuous ubiquitylation of p27(kip1)(p27) by the E3 ligase SCF-Skp2/Cks1 causing its degradation, as a putative mechanism involved pathogenesis this cancer. In contrast, normal intact TGF-β prevents degradation nuclear p27 thereby accumulating block Cdk2 for growth arrest. Here we show ECA cell lines and primary epithelial cells, increases Cdh1 binding APC/C form complex ubiquitylates Cks1 Skp2 prompting their proteasomal thus, leaving intact. Knocking-down increased Skp2/Cks1 activity, completely diminished cytoplasmic p27, obviated TGF-β-mediated inhibition proliferation. Protein synthesis was not required TGF-β-induced increase decrease Skp2. Moreover, half-lives were extended Cdh1-depleted cells. These results suggest levels are strongly or solely regulated degradation. Finally, an inverse relationship low high nucleus shown patients proliferative endometrium grade I-III ECAs whereas differentiated secretory showed reverse. studies implicate master regulator preservation tumor suppressor activity. Thus, is potential therapeutic target other human cancers showing between Cks1/Skp2 and/or dysregulated signaling.