Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
PLoS One. 2012;7(6):e39381. doi: 10.1371/journal.pone.0039381. Epub 2012 Jun 26.
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.
激活素和 TGFβ 共享 SMAD 信号通路，结肠癌可以单独或同时失活这两条通路。激活素和 TGFβ 信号通路在结肠癌中的差异作用尚未被先前剖析。TGFβ 信号通路的一个关键下游靶标是 cdk2 抑制剂 p21(p21(cip1/waf1))。在这里，我们评估了激活素对 p21 调节及其功能的特异性影响。我们发现 TGFβ 是更强的生长抑制诱导剂，而激活素是更强的凋亡诱导剂。此外，两种配体的生长抑制和凋亡都依赖于 SMAD4。然而，激活素以非 SMAD4 依赖的方式下调 p21 蛋白，同时增加泛素化和蛋白酶体降解以增强迁移，而 TGFβ 以 SMAD4 依赖的方式上调 p21 以影响生长停滞。激活素诱导的生长抑制和细胞死亡依赖于 p21，而激活素诱导的迁移则被 p21 抵消。此外，原发性结肠癌显示出与 ACVR2/TGFBR2 受体状态一致的差异 p21 表达。总之，我们报告 p21 是激活素/TGFβ 靶标和配体特异性功能的中介物，这可能被用于未来的风险分层和治疗干预。
