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*
Department of Medicine-Hematology/Oncology;
Graduate School of Biomedical Science,
Department of Obstetrics, Gynecology and Women’s Health,
§
Department of Laboratory Medicine and Pathology, and
¶
Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103
Preprotachykinin-I gene (PPT-I) encodes several
peptides with organ-specific functions that link the
neuroendocrine-immune-hemopoietic 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-1
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 (ICERII
) and activator (CREM
). Mutagenesis of the two
CRE and/or cotransfection with vectors that express ICERII or
CREM 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-1. 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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