Effects of Activin and TGF[beta] 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...

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Bibliographic Details
Published in:PloS one 2012-06, Vol.7 (6), p.e39381
Main Authors: Bauer, Jessica, Sporn, Judith C, Cabral, Jennifer, Gomez, Jessica, Jung, Barbara
Format: Article
Language:English
Subjects:
Apoptosis
Colon cancer
Transforming growth factors
Ubiquitin
Online Access:Get full text
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Summary: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.sup.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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0039381