Abstract
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.
Highlights
IntroductionA member of the TGF1 family, regulates cell growth of various cell types. Activin interacts with a complex of two receptors (types I and II), both containing an extracellular domain, a single transmembrane region, and a large intracellular domain that contain a serine/threonine kinase domain
Activin, a member of the TGF1 family, regulates cell growth of various cell types
We show that activin induces the Smad pathway in these cells and activates the p38-mitogen-activated protein kinase pathway, further leading to phosphorylation of the transcription factor ATF2
Summary
A member of the TGF1 family, regulates cell growth of various cell types. Activin interacts with a complex of two receptors (types I and II), both containing an extracellular domain, a single transmembrane region, and a large intracellular domain that contain a serine/threonine kinase domain. Following binding and phosphorylation by the activin type I receptor, Smad and Smad are released to the cytoplasm where they associate with the common-partner Smad before being translocated to the nucleus (8 –11) Both Smad and Smad but not Smad can directly bind DNA elements (Smad binding element) and activate the transcription of the target genes [12]. In vitro studies suggested that the transcription factor ATF2 could interact with the MH1 domains of two activin responsive Smads, Smad and Smad4 [21, 23] Both TGF and the Mullerian inhibiting substance (MIS) were shown to mediate some of their biological effects through an NFB-mediated pathway [24, 25]. We show here for the first time that activin strongly inhibits cell growth of the
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