Cocolakis E, Lemay S, Ali S, Lebrun J J
Department of Medicine, Royal Victoria Hospital, Molecular Endocrinology Laboratory, McGill University, Montreal H3A 1A1, Canada.
J Biol Chem. 2001 May 25;276(21):18430-6. doi: 10.1074/jbc.M010768200. Epub 2001 Feb 20.
Activin, a member of the TGFbeta family inhibits cell growth in various target tissues. Activin interacts with a complex of two receptors that upon activation phosphorylate specific intracellular mediators, the Smad proteins. The activated Smads interact with diverse DNA binding proteins and co-activators of transcription in a cell-specific manner, thus leading to various activin biological effects. In this study, we investigated the role and mechanism of action of activin in the human breast cancer T47D cells. We found that activin treatment of T47D cells leads to a dramatic decrease in cell growth. Thus activin appears as a potent cell growth inhibitor of these breast cancer cells. We show that activin induces the Smad pathway in these cells but also activates the p38-mitogen-activated protein kinase pathway, further leading to phosphorylation of the transcription factor ATF2. Finally, specific inhibitors of the p38 kinase (SB202190, SB203580, and PD169316) but not an inactive analogue (SB202474) or the MEK-1 inhibitor PD98059 completely abolish the activin-mediated cell growth inhibition of T47D cells. Together, these results define a new role for activin in human breast cancer T47D cells and highlight a new pathway utilized by this growth factor in the mediation of its biological effects in cell growth arrest.
激活素是转化生长因子β家族的成员之一，可抑制多种靶组织中的细胞生长。激活素与两种受体的复合物相互作用，激活后使特定的细胞内介质即Smad蛋白磷酸化。激活的Smad蛋白以细胞特异性方式与多种DNA结合蛋白和转录共激活因子相互作用，从而导致激活素的各种生物学效应。在本研究中，我们调查了激活素在人乳腺癌T47D细胞中的作用及作用机制。我们发现，用激活素处理T47D细胞会导致细胞生长显著下降。因此，激活素似乎是这些乳腺癌细胞的一种强效细胞生长抑制剂。我们表明，激活素在这些细胞中诱导Smad信号通路，但也激活p38丝裂原活化蛋白激酶信号通路，进而导致转录因子ATF2磷酸化。最后，p38激酶的特异性抑制剂（SB202190、SB203580和PD169316），而非无活性类似物（SB202474）或MEK-1抑制剂PD98059，完全消除了激活素介导的T47D细胞生长抑制作用。总之，这些结果确定了激活素在人乳腺癌T47D细胞中的新作用，并突出了这种生长因子在介导其细胞生长停滞生物学效应时所利用的新途径。
