Transforming growth factor-beta signaling in epithelial cells.

Transforming growth factor (TGF)-beta is a potent growth suppressor of epithelial cells. Resistance to TGF-beta, however, occurs frequently in solid tumors of epithelial origin and contributes to the uncontrolled growth of these tumors. Although mutant receptor proteins contribute to TGF-beta insensitivity, deregulation of TGF-beta signaling cascades represents an equally important mechanism underlying TGF-beta resistance. Identification of abnormal regulation of signaling components in tumor epithelial cells will lead to the development of selective therapeutic approaches to repair the relevant signaling cascade(s) and reverse the growth anomaly. Within the past few years, great strides have been made in defining signaling pathways for TGF-beta. For example, our laboratory has demonstrated a direct correlation between TGF-beta-mediated growth inhibition of epithelial cells and activation of Ras and three members of the mitogen-activated protein kinase (MAPK) superfamily. The TGF-beta signaling events were sustained, dose-dependent, and absent in TGF-beta-resistant cells. Further, up-regulation of both p27Kip1 and p21Cip1, nuclear events important for the growth inhibitory effect of TGF-beta, are completely dependent upon the activation of Ras. However, Ras-independent pathways are also activated simultaneously with the Ras/MAPK pathways to mediate the final TGF-beta growth inhibitory outcome. One such pathway includes the SMAD signaling components that control TGF-beta-mediated gene transcription, currently under active study by a number of laboratories, including our own. Future efforts in this field will focus on defining the significance of these signaling proteins and pathways in mediating specific TGF-beta responses. Moreover, additional novel signaling proteins are sure to be identified.