Abstract
Transforming growth factor-beta (TGF-beta) is a potent growth inhibitor of a variety of epithelial cell types. The primary signaling mechanism involved in mediating this and other cellular effects of TGF-beta is still unknown. We report here that both TGF-beta 1 and TGF-beta 2 resulted in a rapid activation of mitogen-activated protein kinase (MAPK) p44mapk, occurring within 5-10 min of growth factor addition. This effect occurred in exponentially proliferating cultures of intestinal epithelial (IEC) 4-1 cells under conditions in which DNA synthesis was inhibited by 95% to 98%. Furthermore, TGF-beta 2 induced a sustained activation of p44mapk under these conditions, lasting for at least 90 min after initial growth factor treatment. Another TGF-beta-sensitive epithelial cell line (CCL 64) displayed a similar rapid increase in p44mapk activity when treated with TGF-beta 1. In contrast, in IEC 4-6 cells that are resistant to TGF-beta effects on growth and DNA synthesis, TGF-beta 2 treatment did not result in an activation of p44mapk. In contrast to the results in proliferating cultures, treatment of quiescent cultures of IEC 4-1 cells with TGF-beta 2 resulted in no significant change in either DNA synthesis or p44mapk activity within 15 min of TGF-beta addition. In contrast, addition of the growth-stimulatory combination of factors (epidermal growth factor + insulin + transferrin = EIT) to quiescent and proliferating IEC 4-1 cells stimulated DNA synthesis and resulted in a sustained activation of p44mapk. Together, our results suggest an association between activation of p44mapk and both TGF-beta-mediated growth inhibition and EIT-mediated growth stimulation. This suggests that the specificity for the cellular effects of growth factors may not occur at the level of MAPK activation per se, but rather at downstream events that include phosphorylation of distinct transcriptional complexes and activation of a select assortment of genes. With regard to TGF-beta specifically, we have proposed a model to explain how activation of p44mapk may be associated with a growth-inhibitory response.
Highlights
Transforming growth factor-p (TGF-tJ) is a potent growth inhibitor of a variety of epithelial cell types
We report here that both TGF-Pl and TGF-P2 resulted in a rapid activation of mitogen-activated protein kinase (MAPK) p44mapk, occurring within 5-10 min of growth factor addition
Another TGF-p-sensitive epithelial cell line (CCL 64) displayed a similar rapid increase in p44mapk activity when treated with TGF-P1" In contrast, in IEC 4-6 cells that are resistant to TGF-p effects on growth and DNA synthesis, TGF·P2 treatment did not result in an activation of p44mapk In contrast to the results in proliferating cultures, treatment of quiescent cultures of IEC 4-1 cells with TGF-P2 resulted in no significant change in either DNA synthesis or p44mapk activity within 15 min ofTGF-p addition
Summary
Transforming Growth Factor 13 Activation of p44m ap k in Proliferating Cultures of Epithelial Cells*. We report here that both TGF-Pl and TGF-P2 resulted in a rapid activation of mitogen-activated protein kinase (MAPK) p44mapk, occurring within 5-10 min of growth factor addition This effect occurred in exponentially proliferating cultures of intestinal epithelial (IEC) 4-1 cells under conditions in which DNA synthesis was inhibited by 95% to 98%. In epithelial cells, TGF-{3 decreases c-myc, p34 cd c2 , cdk, and Bmyb expression [23,24,25,26,27,28,29,30], decreases the phosphorylation of the retinoblastoma protein and p34 cd c2 [31,32,33], increases the expression of c-jun and c-fos [34,35,36], stimulates the phosphorylation of cAMP-responsive element binding protein [37], prevents cdk activation [38], and regulates several G1 cyclins and cell cycle-associated cyclin-cdk inhibitors [39,40,41,42] In contrast to these nuclear effects of TGF-{3, we have reported the first direct evidence for a rapid activation of a cytoplasmic signaling component for TGF-{3in epithelial cells. TGF-f3 did not activate this kinase in proliferating and quiescent cultures of epithelial cells that were resistant to the growth-inhibitory effects of this polypeptide
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
