Regulatory mechanisms in the differential expression of Hemokinin-1.
Hemokinin-1, encoded by the TAC4 gene, is the most recent addition to the tachykinin family. Although most closely related to the neuropeptide Substance P, Hemokinin-1 distinguishes itself from other tachykinins by its predominantly non-neuronal expression pattern. Its expression in T and B lymphocytes, macrophages, and dendritic cells points to an important role for Hemokinin-1 in the immune system. To seek reasons for its preferential expression in the immune system and ultimately to provide clues to its function, we investigated the molecular mechanisms driving the differential expression pattern of this unique tachykinin. Our study provides the first analysis of the promoter region of the TAC4 gene, which reveals regulatory mechanism different from the Substance P promoter. We demonstrate for the first time that Hemokinin-1 initiates transcription from multiple start sites through a TATA-less promoter. Conservation of the 5' non-coding region indicates the importance of the upstream regulatory region in directing expression of Hemokinin-1 in specific cell types, during cell differentiation and activation. Furthermore, NFkappaB, a transcription factor important in the activation of immune cells was shown to be involved in promoting increased TAC4 transcription during PMA induction of a T cell line. Our studies reveal that Hemokinin-1 is regulated by a unique transcription regulation system that likely governs its differential expression pattern and suggests a role for Hemokinin-1 distinct from Substance P.
Tran
Anne H
AH
Department of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, Canada M5G 2M9. anne.tran@utoronto.ca
Berger
Alexandra
A
Wu
Gillian E
GE
Paige
Christopher J
CJ
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D002273:Carcinogens; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D015320:Tachykinins; C507968:hemokinin-1; D005576:Colforsin; D013373:Substance P; D013755:Tetradecanoylphorbol Acetate