| pubmed-article:21131601 | pubmed:abstractText | There are multiple mechanisms by which cells evade TGF-?-mediated growth inhibitory effects. In this report, we describe a novel mechanism by which cells become resistant to TGF-?-mediated growth suppression. Although having all the components of the TGF-? signaling pathway, different cell lines, RL, HaCaT, and BJAB, have different sensitivities toward TGF-?-induced growth suppression. The TGF-? resistance of RL, a B-cell lymphoma cell line, was due to ligand-induced downregulation of TGF-? receptor II (T?RII) and only transient TGF-? induced nuclear translocation of Smad2 and Smad3. With low-dose phorbol 12-myristate 13-acetate (PMA) or anti-IgM treatment, TGF-? sensitivity was restored by stabilizing T?RII expression and sustaining TGF-? signaling. The MEK inhibitor, U0126, blocked both PMA- and anti-IgM-induced upregulation of T?RII. In HaCaT and BJAB, two TGF-?-sensitive cell lines, which had higher basal levels of phospho-MEK and T?RII compared with RL, U0126 induced downregulation of T?RII and blocked subsequent TGF-? signaling. Similar results were also obtained with normal B cells, where MEK1 inhibitor downregulated T?RII and subsequent TGF-? signaling. Constitutively active MEK1, but not constitutively active ERK2, induced upregulation of T?RII. Furthermore, T?RII physically interacted with the constitutively active MEK1, but not with wild-type MEK1, indicating involvement of active MEK1 in stabilizing T?RII. Collectively, our data suggest a novel mechanism for MEK1 in regulating the sensitivity to TGF-? signaling by stabilizing T?RII. | lld:pubmed |
