Abstract
Role of Rho/ROCK and p38 MAP Kinase Pathways in Transforming Growth Factor-β-mediated Smad-dependent Growth Inhibition of Human Breast Carcinoma Cells in Vivo
Highlights
TGF- is a multifunctional cytokine known to exert its biological effects through a variety of signaling pathways of which Smad signaling is considered to be the main mediator
These results indicate that the growth inhibition of these cells by TGF- is accompanied by the up-regulation of p21waf1, hypophosphorylation of pRb and down-regulation of c-Myc protein, events typically associated with inhibition of cell growth by TGF- [49]
Hierarchy of Smad, p38 mitogenactivated protein (MAP) Kinase, and Rho Pathways in Effects of TGF- on Growth Inhibition—Because we demonstrated that both p38 MAPK and Rho/ROCK signaling together with Smad activation are necessary for optimal inhibition of growth of MCF10CA1h cells by TGF-, we decided to investigate the hierarchy of these pathways
Summary
TGF- is a multifunctional cytokine known to exert its biological effects through a variety of signaling pathways of which Smad signaling is considered to be the main mediator. The Smad-independent pathways, their interactions with each other, and their roles in TGF--mediated growth inhibitory effects are not well understood To address these questions, we have utilized a human breast cancer cell line MCF10CA1h and demonstrate that p38 MAP kinase and Rho/ROCK pathways together with Smad and Smad are necessary for TGF--mediated growth inhibition of this cell line. Mutations and/or functional loss of Smad, Smad, and Smad all have been documented [22,23,24,25,26] Whether these changes lead directly to the loss of sensitivity to inhibition of growth by TGF- is not known, it has been shown that in pancreatic carcinoma cell lines resistant to inhibition of growth by TGF-, Smad complexes have a shorter nuclear residence time, which results in an inability to maintain expression of the CDK inhibitor, p21waf1 [14]. Recent data suggest that aberrant activation of MAP kinase pathways may play an important role in diverting
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