tailieunhanh - Báo cáo khoa học: Snail associates with EGR-1 and SP-1 to upregulate transcriptional activation of p15INK4b

Snail is a multifunctional transcriptional factor that has been described as a repressor in many different contexts. It is also proposed as an activator in a few cases relevant to tumor progression and cell-cycle arrest. This study investigated the detailed mechanisms by which Snail upregulates gene expression of the CDK inhibitor p15 INK4b in HepG2 induced by the tumor promoter tetradecanoyl phorbol acetate (TPA). | ễFEBS Journal Snail associates with EGR-1 and SP-1 to upregulate transcriptional activation of p15INK4b Chi-Tan Hu1 Tsu-Yao Chang2 Chuan-Chu Cheng2 Chun-Shan Liu2 Jia-Ru Wu2 Ming-Che Li1 and Wen-Sheng Wu2 1 Research Centre for Hepatology Buddhist Tzu Chi GeneralHospitaland Tzu Chi University Hualien Taiwan 2 Institute of MedicalBiotechnology College of Medicine Tzu Chi University Hualein Taiwan Keywords EGR-1 p15INK4b Snail SP-1 transcriptional regulation Correspondence Wen-Sheng Wu Institute of Medical Biotechnology College of Medicine Tzu Chi University No. 701 Chung Yang Rd Sec 3 Hualien 970 Taiwan Fax 8867 03 8571917 Tel 8867 03 8565301 ext. 2327 E-mail wuwstcu1234@ Received 10 October 2009 revised 10 December 2009 accepted 18 December 2009 doi Snail is a multifunctional transcriptional factor that has been described as a repressor in many different contexts. It is also proposed as an activator in a few cases relevant to tumor progression and cell-cycle arrest. This study investigated the detailed mechanisms by which Snail upregulates gene expression of the CDK inhibitor p15INK4b in HepG2 induced by the tumor promoter tetradecanoyl phorbol acetate TPA . Using deletion mapping the TPA-responsive element on the p15INK4b promoter was located between 77 and 228 bp upstream of the transcriptional initiation site within which the putative binding regions of early growth response gene 1 EGR-1 and stimulatory protein 1 SP-1 were found. Gene expression of EGR-1 Snail and SP-1 can be induced by TPA within h. In addition basal levels of SP-1 but not of the other two transcriptional factors were observed. Blockade of TPA-induced gene expression of Snail EGR-1 or SP-1 suppressed activation of the p15-pro228 reporter plasmid harboring the TPA-responsive element. More detailed deletion mapping and site-directed mutagenesis further concluded that the overlapping EGR-1 SP-1-binding site was required for TPA-induced p15-pro228 .