Tac1 regulation by RNA-binding protein and miRNA in bone marrow stroma: Implication for hematopoietic activity.
Hematopoiesis is the process by which immune and blood cells are produced from a finite number of relatively few hematopoietic stem cells (HSCs). In adults, hematopoiesis occurs in the adult bone marrow (BM), with the support of stromal cells. This support partly occurs through the production of hematopoietic regulators belonging to the families of cytokines and neuropeptides/neurotransmitters, which mediate their actions through specific receptors. Thus, stromal cells could be central to the neural-hematopoietic-immune axis. This study focuses on Tac1, which encodes hematopoietic regulators belonging to the tachykinin family of neuropeptides. We examined post-transcriptional regulation of Tac1 in BM stroma. Since this gene is inducible in stroma, we selected cytokines with varying hematopoietic effects: stimulator Stem Cell Factor (SCF), broad-acting IL-11 and suppressive TGF-beta1. RNA shift with Tac1 mRNA and cytoplasmic extracts from IL-11 and SCF-stimulated stroma showed RNA shift after 15min at 37 degrees C, whereas a shift was detected with extracts from TGF-beta1-stimulated stroma after 5min at room temperature. Another level of post-transcriptional regulation was observed by the detection of miRNAs that interact with the 3' untranslated region of Tac1 mRNA. In summary, this study showed that cytokine induced miRNA downregulation and RNA-binding protein(s) are involved in post-transcriptional regulation of Tac1 in BM stroma. The broad categories of cytokines as hematopoietic stimulators or inhibitors might depend on the avidity of RNA-binding protein(s) for Tac1 mRNA, as well as the ability to degrade or stabilize the specific miRNAs.
Murthy
Raghav G
RG
UMDNJ-New Jersey Medical School, MSB, Room E-579, 185 South Orange Ave, Newark, NJ 07103, USA.
Greco
Steven J
SJ
Taborga
Marcelo
M
Patel
Nitixa
N
Rameshwar
Pranela
P
D020413:3' Untranslated Regions / Q000502:physiology; D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D017930:Genes, Reporter; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D017370:Interleukin-11 / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D015213:Neuroimmunomodulation / Q000235:genetics / Q000502:physiology; D015288:Neurokinin A / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology; D013373:Substance P / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D020413:3' Untranslated Regions; D017370:Interleukin-11; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015320:Tachykinins; D053773:Transforming Growth Factor beta1; D013373:Substance P; D017228:Hepatocyte Growth Factor; D015288:Neurokinin A