Cloning of human preprotachykinin-I promoter and the role of cyclic adenosine 5′-monophosphate response elements in its expression by IL-1 and stem cell factor

J. Qian, G. Yehia, Carlos Molina, A. Fernandes, R. J. Donnelly, D. J. Anjaria, P. Gascon, P. Rameshwar

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Abstract

Preprotachykinin-I gene (PPT-I) encodes several peptides with organ-specific functions that link the neuroendocrine-immunehemopoietic axis. We cloned upstream of the initiation site of human PPT-I promoter and identified consensus sequences for two cAMP response elements (CRE). PPT-I is induced by cytokines including those that signal through the cAMP pathway. Therefore, we studied the role of the two CRE in IL-1α and stem cell factor (SCF) stimulation of bone marrow stroma because both cytokines induce endogenous PPT-I in these cells and activate the cAMP pathway. Furthermore, bone marrow stroma expresses the transcription factors regulated by the cAMP pathways such as the repressor (ICERIIγ) and activator (CREMτ). Mutagenesis of the two CRE and/or cotransfection with vectors that express ICERIIγ or CREMτ indicated that the two CRE have major roles in PPT-I expression. The two CRE are also required for optimal promoter activity by SCF and IL-1α. A particular cytokine could concomitantly induce PPT-I and the high affinity G protein-coupled receptor for PPT-I peptides, NK-1R. We showed that SCF, a representative cytokine, induced PPT-I and NK-1R leading to autocrine and/or paracrine cell activation. Because NK-1R activates cAMP through the G protein, the results suggest that the presence of CRE sequences within PPT-I promoter could be important in the regulation of PPT-I expression by cytokines, irrespective of their ability to signal through cAMP. As PPT-I is implicated in hemopoietic regulation, immune responses, breast cancer, and other neural functions, these studies add to the basic biology of these processes and could provide targets for drug development.

Original languageEnglish
Pages (from-to)2553-2561
Number of pages9
JournalJournal of Immunology
Volume166
Issue number4
DOIs
StatePublished - 15 Feb 2001

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Stem Cell Factor
Response Elements
Interleukin-1
Cyclic AMP
Organism Cloning
Genes
Cytokines
preprotachykinin
Bone Marrow
Gene Expression
Peptides
Consensus Sequence
G-Protein-Coupled Receptors
GTP-Binding Proteins
Mutagenesis
Transcription Factors
Breast Neoplasms

Cite this

Qian, J. ; Yehia, G. ; Molina, Carlos ; Fernandes, A. ; Donnelly, R. J. ; Anjaria, D. J. ; Gascon, P. ; Rameshwar, P. / Cloning of human preprotachykinin-I promoter and the role of cyclic adenosine 5′-monophosphate response elements in its expression by IL-1 and stem cell factor. In: Journal of Immunology. 2001 ; Vol. 166, No. 4. pp. 2553-2561.
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abstract = "Preprotachykinin-I gene (PPT-I) encodes several peptides with organ-specific functions that link the neuroendocrine-immunehemopoietic axis. We cloned upstream of the initiation site of human PPT-I promoter and identified consensus sequences for two cAMP response elements (CRE). PPT-I is induced by cytokines including those that signal through the cAMP pathway. Therefore, we studied the role of the two CRE in IL-1α and stem cell factor (SCF) stimulation of bone marrow stroma because both cytokines induce endogenous PPT-I in these cells and activate the cAMP pathway. Furthermore, bone marrow stroma expresses the transcription factors regulated by the cAMP pathways such as the repressor (ICERIIγ) and activator (CREMτ). Mutagenesis of the two CRE and/or cotransfection with vectors that express ICERIIγ or CREMτ indicated that the two CRE have major roles in PPT-I expression. The two CRE are also required for optimal promoter activity by SCF and IL-1α. A particular cytokine could concomitantly induce PPT-I and the high affinity G protein-coupled receptor for PPT-I peptides, NK-1R. We showed that SCF, a representative cytokine, induced PPT-I and NK-1R leading to autocrine and/or paracrine cell activation. Because NK-1R activates cAMP through the G protein, the results suggest that the presence of CRE sequences within PPT-I promoter could be important in the regulation of PPT-I expression by cytokines, irrespective of their ability to signal through cAMP. As PPT-I is implicated in hemopoietic regulation, immune responses, breast cancer, and other neural functions, these studies add to the basic biology of these processes and could provide targets for drug development.",
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Cloning of human preprotachykinin-I promoter and the role of cyclic adenosine 5′-monophosphate response elements in its expression by IL-1 and stem cell factor. / Qian, J.; Yehia, G.; Molina, Carlos; Fernandes, A.; Donnelly, R. J.; Anjaria, D. J.; Gascon, P.; Rameshwar, P.

In: Journal of Immunology, Vol. 166, No. 4, 15.02.2001, p. 2553-2561.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Cloning of human preprotachykinin-I promoter and the role of cyclic adenosine 5′-monophosphate response elements in its expression by IL-1 and stem cell factor

AU - Qian, J.

AU - Yehia, G.

AU - Molina, Carlos

AU - Fernandes, A.

AU - Donnelly, R. J.

AU - Anjaria, D. J.

AU - Gascon, P.

AU - Rameshwar, P.

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