The anti-proliferative effect of neurokinin-A on hematopoietic progenitor cells is partly mediated by p53 activating the 5' flanking region of neurokinin-2 receptor.
The bone marrow (BM) is home to at least two stem cells, hematopoietic (HSC) and mesenchymal. Hematopoiesis is partly regulated through neurokinin-1 (NK-1) and NK-2 belonging to the family of G-protein/7-transmembrane receptors. NK-1 and NK-2 show preference for the neurotransmitters, substance P (SP) and neurokinin-A (NK-A), respectively. Hematopoietic suppression mediated by NK-A could be partly explained through the production of TGF-beta1 and MIP-1alpha. This study further characterizes mechanisms by which NK-A inhibits progenitor cell proliferation. The study addresses the hypothesis that p53 is a mediator of NK-A activation and this occurs partly through p53-mediated expression of NK-2. The studies first analyzed two consensus sequences for p53 in supershift assays. Reporter gene assays with NK-2 gene constructs and p53 expressing wild-type and mutant vectors, combined with cell proliferation assays, show NK-A activating p53 to inhibit the proliferation of K562 progenitors. These effects were reversed by hematopoietic stimulators, GM-CSF and SP. Verification studies with human CD34+/CD38- and CD34+/CD38+ BM progenitors show similar mechanisms with the expression of p21. This study reports on p53 as central to NK-A-NK-2 interaction in cell cycle quiescence of hematopoietic progenitors. These effects are reversed by at least two hematopoietic stimulators, SP and GM-CSF, with concomitant downregulation of p53.
Vishalakumar
Suvarnamala
S
Graduate School of Biomedical Sciences, UMDNJ, NJ, USA.
Patel
Hiral
H
Moharita
Anabella L
AL
Harrison
Jonathan S
JS
Rameshwar
Pranela
P
D024506:5' Flanking Region / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D015288:Neurokinin A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D018041:Receptors, Neurokinin-2; D016159:Tumor Suppressor Protein p53; D013373:Substance P; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015288:Neurokinin A