TY - JOUR
T1 - Repression of transcription of the p27Kip1 cyclin-dependent kinase inhibitor gene by c-Myc
AU - Yang, William
AU - Shen, Jian
AU - Wu, Min
AU - Arsura, Marcello
AU - FitzGerald, Mark
AU - Suldan, Zalman
AU - Kim, Dong W.
AU - Hofmann, Claudia S.
AU - Pianetti, Stefania
AU - Romieu-Mourez, Raphaëlle
AU - Freedman, Leonard P.
AU - Sonenshein, Gail E.
N1 - Funding Information:
We thank Drs C Dang, S Desiderio, S Hann, A Koff, Y Xiong, and E Ziff for generously providing cloned DNAs or antibody preparations. This work was supported by National Institutes of Health grants CA 36355 (GE Sonenshein), HL13262 (GE Sonenshein), and CA 82742 (GE Sonenshein) and training grants HL07429 (W Yang) and CA64070 (MJ FitzGerald), and Department of Army grant DAMD17-98-1-8034 (DW Kim) and Cure for Lymphoma Foundation (M Arsura).
PY - 2001/3/29
Y1 - 2001/3/29
N2 - Upon engagement of the B Cell Receptor (BCR) of WEHI 231 immature B cells, a drop in c-Myc expression is followed by activation of the cyclin-dependent kinase inhibitor (CKI) p27Kip1, which induces growth arrest and apoptosis. Here, we report inverse patterns of p27 and c-Myc protein expression follow BCR engagement. We present evidence demonstrating, for the first time, that the p27Kip1 gene is a target of transcriptional repression by c-Myc. Specifically, the changes in p27 protein levels correlated with changes in p27 mRNA levels, and gene transcription. Induction of p27 promoter activity followed BCR engagement of WEHI 231 cells, and this induction could be repressed upon co-transfection of a c-Myc expression vector. Inhibition of the TATA-less p27 promoter by c-Myc was also observed in Jurkat T cells, vascular smooth muscle, and Hs578T breast cancer cells, extending the observation beyond immune cells. Consistent with a putative Inr element CCAGACC (where + 1 is underlined) at the start site of transcription in the p27 promoter, deletion of Myc homology box II reduced the extent of repression. Furthermore, enhanced repression was observed upon transfection of the c-Myc 'superrepressor', with mutation of Phe115 to Leu. The sequences mediating transcriptional activity and c-Myc repression were mapped to bp -20 to + 20 of the p27 gene. Finally, binding of Max was shown to facilitate e-Myc binding and repression of p27 promoter activity. Overall, these studies identify the p27 CKl gene as a new target whereby c-Myc can control cell proliferation, survival and neoplastic transformation.
AB - Upon engagement of the B Cell Receptor (BCR) of WEHI 231 immature B cells, a drop in c-Myc expression is followed by activation of the cyclin-dependent kinase inhibitor (CKI) p27Kip1, which induces growth arrest and apoptosis. Here, we report inverse patterns of p27 and c-Myc protein expression follow BCR engagement. We present evidence demonstrating, for the first time, that the p27Kip1 gene is a target of transcriptional repression by c-Myc. Specifically, the changes in p27 protein levels correlated with changes in p27 mRNA levels, and gene transcription. Induction of p27 promoter activity followed BCR engagement of WEHI 231 cells, and this induction could be repressed upon co-transfection of a c-Myc expression vector. Inhibition of the TATA-less p27 promoter by c-Myc was also observed in Jurkat T cells, vascular smooth muscle, and Hs578T breast cancer cells, extending the observation beyond immune cells. Consistent with a putative Inr element CCAGACC (where + 1 is underlined) at the start site of transcription in the p27 promoter, deletion of Myc homology box II reduced the extent of repression. Furthermore, enhanced repression was observed upon transfection of the c-Myc 'superrepressor', with mutation of Phe115 to Leu. The sequences mediating transcriptional activity and c-Myc repression were mapped to bp -20 to + 20 of the p27 gene. Finally, binding of Max was shown to facilitate e-Myc binding and repression of p27 promoter activity. Overall, these studies identify the p27 CKl gene as a new target whereby c-Myc can control cell proliferation, survival and neoplastic transformation.
KW - Breast cancer
KW - Max
KW - Smooth muscle cells
KW - WEHI 231 cells
KW - c-Myc
KW - p27
UR - http://www.scopus.com/inward/record.url?scp=0035967099&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035967099&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1204245
DO - 10.1038/sj.onc.1204245
M3 - Article
C2 - 11313917
AN - SCOPUS:0035967099
SN - 0950-9232
VL - 20
SP - 1688
EP - 1702
JO - Oncogene
JF - Oncogene
IS - 14
ER -