Effects of Activin and TGFβ on p21 in Colon Cancer

Activin and TGF beta share SMAD signaling and colon cancers can inactivate either pathway alone or simultaneously. The differential effects of activin and TGF beta signaling in colon cancer have not been previously dissected. A key downstream target of TGF beta signaling is the cdk2 inhibitor p21 (p21(cip1/waf1)). Here, we evaluate activin-specific effects on p21 regulation and resulting functions. We find that TGF beta is a more potent inducer of growth suppression, while activin is a more potent inducer of apoptosis. Further, growth suppression and apoptosis by both ligands are dependent on SMAD4. However, activin downregulates p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination and proteasomal degradation to enhance migration, while TGF beta upregulates p21 in a SMAD4-dependent fashion to affect growth arrest. Activin-induced growth suppression and cell death are dependent on p21, while activin-induced migration is counteracted by p21. Further, primary colon cancers show differential p21 expression consistent with their ACVR2/TGFBR2 receptor status. In summary, we report p21 as a differentially affected activin/TGF beta target and mediator of ligand-specific functions in colon cancer, which may be exploited for future risk stratification and therapeutic intervention.