| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 98 === The transcription factor Sp1 is ubiquitously expressed in different cells and thereby regulates the expression of genes involved in many cellular processes. In this study, we found that JNK1 was activated during mitosis, and then caused Sp1 to be phosphorylated form. JNK1 phosphorylated Sp1 at Thr278 and Thr 739, thereby increasing the Sp1 stability by repressing the Sp1 degradation in the proteasome- dependent pathway. These results characterize the stability of Sp1 and suggest a tumorigenic action of Sp1. In addition, we also found that Sp1 is a new substrate of CDK1 and is phosphorylated at Thr739 before the entry of mitosis. Further, during mitosis, Pin1, a peptidyl-prolyl isomerase, shields phospho-Sp1-Thr739 from dephosphorylation by PP2A via an action involving the isomerase activity of Pin1. Phospho-Sp1 loses its affinity for DNA and appears to exist as a congregated ring in the periphery of chromosomes. At the end of mitosis and the beginning of interphase however, Sp1 becomes dephosphorylated by PP2A and returns to the chromatin. The results indicate that cancer cells utilize Pin1 to stabilize Sp1 in phosphorylated form and recycle the latter between mitosis and interphase. Pin1 thus, by stabilizing phospho-Sp1, serves to facilitate the quick initiation and execution of interphase in order to maintain the favorable proliferative nature of cancer cells. In MNU-induced mammary tumors, we also found the high Pin 1, CDK1, and JNK1 activation and a high Sp1 accumulation. However, we also found that incompletely phosphorylated Sp1 could block global chromatin condensation and led to a type of DNA-packaging stress. Finaly, the incompletely phosphorylated Sp1 induced cell apoptosis when cells entered the mitotic stage. In conclusion, phosphorylation could play some important roles to regulate the DNA binding ability, transcription activity, and protein stability of Sp1 during mitosis.
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