Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene.
PAC-1, an early-response gene originally identified in activated T cells, encodes a dual-specificity mitogen-activated protein kinase phosphatase. Here we report on the regulation of PAC-1 expression in murine hemopoietic cells. PAC-1 mRNA levels rapidly increase in mitogen-stimulated lymphocytes, with the induced expression being transient in B cells but sustained in activated T cells. Transfection analysis of murine PAC-1 promoter-reporter constructs established that in T cells, sequences necessary for basal and induced transcription reside within a 200-bp region located immediately upstream of the transcription initiation sites. Basal transcription is regulated in part by an E-box element that binds a 53-kDa protein. PAC-1 transcription induced by phorbol myristate acetate stimulation and the expression of the v-ras or v-raf oncogene is mediated via the E-box motif and an AP-2-related site and coincides with increased binding activity of the constitutive 53-kDa E-box-binding protein and induced binding of AP-2. The ability of an interfering ERK-2 mutant to block phorbol myristate acetate and v-ras-dependent PAC-1 transcription indicates that mitogen-activated protein kinase activation is necessary for these stimuli to induce transcription of the PAC-1 gene in T cells.
Grumont
R J
RJ
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Rasko
J E
JE
Strasser
A
A
Gerondakis
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D015342:DNA Probes / Q000235:genetics; D054641:Dual Specificity Phosphatase 2; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006410:Hematopoiesis / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D027384:Oncogene Proteins v-raf; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000494:pharmacology; D013601:T-Lymphocytes / Q000201:enzymology; D014158:Transcription, Genetic / Q000187:drug effects; D018631:ras Proteins / Q000494:pharmacology
D015342:DNA Probes; D012333:RNA, Messenger; D015682:Retroviridae Proteins, Oncogenic; D027384:Oncogene Proteins v-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054648:Protein Phosphatase 2; D054641:Dual Specificity Phosphatase 2; C517033:Dusp2 protein, mouse; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins