Abstract
We have recently shown that induction of biglycan (BGN) expression by transforming growth factor-beta1 (TGF-beta1) required sequential activation of both Smad and p38 mitogen-activated protein kinase signaling (Ungefroren, H., Lenschow, W., Chen, W.-B., and Kalthoff, H. (2003) J. Biol. Chem. 278, 11041-11049). Here, we have analyzed the receptors through which TGF-beta1 controls expression of BGN and GADD45beta, the latter of which is postulated to link early Smad signaling to delayed activation of p38. Ectopic expression of a dominant-negative mutant of the TGF-beta type II receptor in PANC-1 cells abrogated TGF-beta-induced BGN up-regulation. Similarly, inhibition of the TGF-beta type I receptor/ALK5 with either SB431542 or by enforced stable expression of a kinase-dead mutant greatly attenuated the TGF-beta effect on both BGN and GADD45beta expression in PANC-1 and MG-63 cells. The enhancing effect of ALK5 on TGF-beta-mediated GADD45beta and BGN expression and on GADD45beta promoter activity was also dependent on its ability to activate Smad signaling, because an ALK5 mutant defective in Smad activation (TbetaRImL45) but with an otherwise functional kinase domain failed to mediate these responses. The TGF-beta/ALK5 effect on p38 activation and BGN expression was mimicked by overexpression of GADD45beta alone (in the absence of TGF-beta stimulation) and suppressed upon antisense inhibition of GADD45beta expression. These results show that TGF-beta induces BGN expression through (the Smad-activating function of) ALK5 and GADD45beta and suggest that the sensitivity of MyD118 to activation by TGF-beta, which varies between tissues, ultimately determines the strength of the TGF-beta effect on BGN.
Highlights
transforming growth factor-1 (TGF-1) and its signaling effectors regulate basic cellular functions such as proliferation and apoptosis and act as key determinants of tumor cell behavior (1–3)
GADD45 Activates p38 mitogen-activated protein kinases (MAPKs) and Enhances BGN Expression—Having demonstrated that GADD45 expression is induced by TGF- via ALK5, we investigated whether ectopic overexpression of GADD45 could activate p38 and upregulate BGN in the absence of TGF- stimulation
In this study we have analyzed the role of ALK5 in TGF- regulation of GADD45 and BGN in PANC-1 and MG-63 cells
Summary
TGF-1 and its signaling effectors regulate basic cellular functions such as proliferation and apoptosis and act as key determinants of tumor cell behavior (1–3). Very similar results with respect to BGN expression were obtained with PANC-1 cells ectopically expressing caALK5 or caTRImL45 (data not shown; these cells were used for analysis of TGF-/ALK5 regulation of GADD45 expression, see Fig. 4C).
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