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Effects of activin and TGFβ on p21 in colon cancer.

Bauer J, Sporn JC, Cabral J, Gomez J, Jung B - PLoS ONE (2012)

Bottom Line: Here, we evaluate activin-specific effects on p21 regulation and resulting functions.However, activin downregulates p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination and proteasomal degradation to enhance migration, while TGFβ 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT
Activin and TGFβ share SMAD signaling and colon cancers can inactivate either pathway alone or simultaneously. The differential effects of activin and TGFβ signaling in colon cancer have not been previously dissected. A key downstream target of TGFβ signaling is the cdk2 inhibitor p21 (p21(cip1/waf1)). Here, we evaluate activin-specific effects on p21 regulation and resulting functions. We find that TGFβ 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 TGFβ 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/TGFβ target and mediator of ligand-specific functions in colon cancer, which may be exploited for future risk stratification and therapeutic intervention.

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Expression of p21 is lost in a subset of primary colon cancers correlating with the ACVR2/TGFBR2 receptor status.Fifty-six colon cancers were stained for ACVR2, TGFBR2 and p21. Representative examples for p21 staining are shown: normal colon tissue with nuclear staining (left panel), colon cancer sample with maintained nuclear p21 staining (middle panel), and colon cancer sample with loss of nuclear p21 staining (right panel).
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pone-0039381-g006: Expression of p21 is lost in a subset of primary colon cancers correlating with the ACVR2/TGFBR2 receptor status.Fifty-six colon cancers were stained for ACVR2, TGFBR2 and p21. Representative examples for p21 staining are shown: normal colon tissue with nuclear staining (left panel), colon cancer sample with maintained nuclear p21 staining (middle panel), and colon cancer sample with loss of nuclear p21 staining (right panel).

Mentions: We then assessed whether impaired activin/TGFβ signaling affected p21 localization in primary colon cancers. We determined presence versus loss of nuclear p21 expression in 56 primary colon cancer specimens of various genomic subtypes, and correlated this data with the activin and TGFβ receptor status (Table 1). We found that a large subset of colon cancers showed loss of nuclear p21, and that this loss was associated with preservation of ACVR2 (Table 1 and Figure 6), suggesting decreased signaling through the SMAD4/p21 axis, but intact activin SMAD4-independent signaling. The opposite was the case for TGFBR2: Preservation of TGFBR2 was associated with persistent nuclear p21 (Table 1). This data is consistent with our in vitro findings of TGFβ/SMAD4-dependent upregulation of p21 and activin/non-SMAD4-dependent downregulation of p21.


Effects of activin and TGFβ on p21 in colon cancer.

Bauer J, Sporn JC, Cabral J, Gomez J, Jung B - PLoS ONE (2012)

Expression of p21 is lost in a subset of primary colon cancers correlating with the ACVR2/TGFBR2 receptor status.Fifty-six colon cancers were stained for ACVR2, TGFBR2 and p21. Representative examples for p21 staining are shown: normal colon tissue with nuclear staining (left panel), colon cancer sample with maintained nuclear p21 staining (middle panel), and colon cancer sample with loss of nuclear p21 staining (right panel).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3383701&req=5

pone-0039381-g006: Expression of p21 is lost in a subset of primary colon cancers correlating with the ACVR2/TGFBR2 receptor status.Fifty-six colon cancers were stained for ACVR2, TGFBR2 and p21. Representative examples for p21 staining are shown: normal colon tissue with nuclear staining (left panel), colon cancer sample with maintained nuclear p21 staining (middle panel), and colon cancer sample with loss of nuclear p21 staining (right panel).
Mentions: We then assessed whether impaired activin/TGFβ signaling affected p21 localization in primary colon cancers. We determined presence versus loss of nuclear p21 expression in 56 primary colon cancer specimens of various genomic subtypes, and correlated this data with the activin and TGFβ receptor status (Table 1). We found that a large subset of colon cancers showed loss of nuclear p21, and that this loss was associated with preservation of ACVR2 (Table 1 and Figure 6), suggesting decreased signaling through the SMAD4/p21 axis, but intact activin SMAD4-independent signaling. The opposite was the case for TGFBR2: Preservation of TGFBR2 was associated with persistent nuclear p21 (Table 1). This data is consistent with our in vitro findings of TGFβ/SMAD4-dependent upregulation of p21 and activin/non-SMAD4-dependent downregulation of p21.

Bottom Line: Here, we evaluate activin-specific effects on p21 regulation and resulting functions.However, activin downregulates p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination and proteasomal degradation to enhance migration, while TGFβ 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT
Activin and TGFβ share SMAD signaling and colon cancers can inactivate either pathway alone or simultaneously. The differential effects of activin and TGFβ signaling in colon cancer have not been previously dissected. A key downstream target of TGFβ signaling is the cdk2 inhibitor p21 (p21(cip1/waf1)). Here, we evaluate activin-specific effects on p21 regulation and resulting functions. We find that TGFβ 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 TGFβ 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/TGFβ target and mediator of ligand-specific functions in colon cancer, which may be exploited for future risk stratification and therapeutic intervention.

Show MeSH
Related in: MedlinePlus