No abstract

The transforming growth factor ,Bs (TGF-,Bs) are a group of multifunctional growth factors which inhibit cell cycle progression in many cell types. The TGF-,pinduced cell cycle arrest has been partially attributed to the regulatory effects of TGF-j8 on both the levels and the activities of the G1 cyclins and their kinase partners. The activities of these kinases are negatively regulated by a number of small proteins, p21 (WAFi, Cipl), p27KiPl, p16, and p15INK4B, that physically associate with cyclins, cyclindependent kinases, or cyclin-Cdk complexes. p21 has been previously shown to be transcriptionally induced by DNA damage through p53 as a mediator. We demonstrate that TGF-13 also causes a rapid transcriptional induction of p21, suggesting that p21 can respond to both intracellular and extracellular signals for cell cycle arrest. In contrast to DNA damage, however, induction of p21 by TGF-j3 is not dependent on wild-type p53. The cell line studied in these experiments, HaCaT, contains two mutant alleles of p53, which are unable to activate transcription from the p21 promoter when overexpressed. In addition, TGF-j3 and p53 act through distinct elements in the p21 promoter. Taken together, these findings suggest that TGF-j8 can induce p21 through a p53-independent pathway. Previous findings have implicated p27KiP' and p15INK2B as effectors mediating the TGF-f3 growth inhibitory effect. These results demonstrate that a single extracellular antiproliferative signal, TGF-j8, can act through multiple signaling pathways to elicit a growth arrest response.

Molecular mechanisms associated with tumor metastasis remain poorly understood. Here we report that acquired expression of periostin by colon cancer cells greatly promoted metastatic development of colon tumors. Periostin is overexpressed in more than 80% of human colon cancers examined with highest expression in metastatic tumors. Periostin expression dramatically enhanced metastatic growth of colon cancer by both preventing stress-induced apoptosis in the cancer cells and augmenting endothelial cell survival to promote angiogenesis. At the molecular level, periostin activated the Akt/PKB signaling pathway through the alpha(v)beta(3) integrins to increase cellular survival. These data demonstrated that the survival-promoting function is crucial for periostin to promote tumor metastasis of colon cancer.