role of t198 modification in the regulation of p27kip1 protein stability and functiont198修改在p27kip1蛋白质的稳定性和功能的调节.pdfVIP

Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function . . Monica Schiappacassi , Sara Lovisa , Francesca Lovat, Linda Fabris, Alfonso Colombatti, Barbara Belletti, Gustavo Baldassarre* Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy Abstract The tumor suppressor gene p27Kip1 plays a fundamental role in human cancer progression. Its expression and/or functions are altered in almost all the different tumor histotype analyzed so far. Recently, it has been demonstrated that the tumor suppression function of p27 resides not only in the ability to inhibit Cyclins/CDKs complexes through its N-terminal domain but also in the capacity to modulate cell motility through its C-terminal portion. Particular interest has been raised by the last amino-acid, (Threonine 198) in the regulation of both protein stability and cell motility. Here, we describe that the presence of Threonine in position 198 is of primary importance for the regulation of the protein stability and for the control of cell motility. However, while the control of cell motility is dependent on the phosphorylation of T198, the stability of the protein is specifically controlled by the steric hindrance of the last amino acid. The effects of T198 modification on protein stability are not linked to the capacity of p27 to bind Cyclins/CDKs complexes and/or the F-box protein Skp2. Conversely, our results support the hypothesis that conformational changes in the disordered structure of the C-terminal portion of p27 are important in its ability to be degraded via a proteasome-dependent mechanism. On the other hand T198 phosphorylation favors p27/stathmin interaction eventually contributing to the reg