A novel Smad-independent pathway is responsible for escape from TGFbeta-induced growth inhibition in Tβ RII mutation (T315M) associated with HNPCC Free

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It is generally accepted that the Smads mediate tranforming growth factor-β

(TGFβ) signaling to inhibit cell proliferation, while several Smad4-defective cell lines retain certain levels of responsiveness to TGFb, suggesting additional signaling pathway for cell cycle arrest. We have previously shown that protein phosphatase 2A (PP2A) is directly associated with TβR, released into the cytosol upon TGFβ stimulation, and dephosphrylated p53 (S376), indicated that PP2A and p53 are involved in the TGFβ-mediated signaling for growth inhibition. Recently, TβRII mutation (T315M), which was impaired to emit signal of TGFβ, was found in a kindred of HNPCC without microsatellite instability (Nature Gene, 1992). Here we demonstrate that PP2A-p53 signaling pathway was not activated in the TbRII (T315M) transfected cells (DR/T315M). In DR/T315M cells, upon TGFb stimulation, p53 as well as PP2A was not activated. By contrast, when DR/T315M cells were transfected with p53 (S376A), which can mimic dephosphorylated form, the growth of cells was suppressed by TGFβ. These results define a novel pathway for TGFβ mediated-cell growth arrest, which is distinct from the Smad-independent pathway, and suggests that loss of p53 and PP2A function is one of the mechanisms for escape from negative growth regulation by TGFβ
 >in certain cancer cells.