TGFbeta regulated gene expression by Smads and Sp1/KLF-like transcription factors in cancer

Abstract

Transforming growth factor beta (TGFbeta) controls vital cellular functions through its ability to regulate gene expression. TGFbeta binding to its transmembrane receptor kinases initiates distinct intracellular signalling cascades including the Smad signalling and transcription factors and also Smad-independent pathways. In normal epithelial cells, TGFbeta stimulation induces a cytostatic program which includes the transcriptional repression of the c-Myc oncogene and the later induction of the cell cycle inhibitors p15(INK4b) and p21(Cip1). During carcinogenesis, however, many tumor cells lose their ability to respond to TGFbeta with growth inhibition, and instead, activate genes involved in cell proliferation, invasion and metastasis. Strong efforts have been made during recent years to characterize Smad-mediated transcriptional processes and to identify those TGFbeta-regulated transcription factors that control gene expression independent of the Smads. These studies have led to the identification of a novel family of TGFbeta-inducible Sp1/KLF-(Krüppel-like factors) like transcription factors (KLF10 and KLF11) which play remarkable roles in TGFbeta mediated cell growth control and differentiation. In this article, the current knowledge on the peculiar roles of Sp1/KLF-like proteins in Smad dependent and -independent gene regulation initiated by TGFbeta, are summarized.