Regulation of murine hematopoietic stem cell quiescence by Dmtf1.
The cell-cycle status of hematopoietic stem cells (HSCs) is tightly regulated, most likely to balance maintenance of stem-cell status through quiescence and expansion/differentiation of the hematopoietic system. Tumor-suppressor genes (TSGs), with their cell cycle-regulatory functions, play important roles in HSC regulation. The cyclin-D binding myb-like transcription factor 1 (Dmtf1) was recently recognized as a TSG involved in human cancers by repressing oncogenic Ras/Raf signaling. However, the role of Dmtf1 in the hematopoietic system is entirely unknown. In the present study, we demonstrate that Dmtf1 regulates HSC function under both steady-state and stress conditions. Dmtf1(-/-) mice showed increased blood cell counts in multiple parameters, and their progenitor cells had increased proliferation and accelerated cell-cycle progression. In addition, long-term HSCs from Dmtf1(-/-) mice had a higher self-renewal capacity that was clearly demonstrated in secondary recipients in serial transplantation studies. Dmtf1(-/-) BM cells showed hyper proliferation after 5-fluorouracil-induced myeloablation. Steady-state expression and Induction of CDKN1a (p21) and Arf were impaired in HSCs from Dmtf1(-/-) mice. The function of Dmtf1 was mediated by both Arf-dependent and Arf-independent pathways. Our results implicate Dmtf1 in the regulation of HSC function through novel cell cycle-regulatory mechanisms.
Department of Medicine, Indiana University School of Medicine, 980 West Walnut St., Indianapolis, IN 46202, USA.
Michihiro
M
Kobayashi
Edward F
EF
Srour
D000818:Animals; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C102116:Dmtf1 protein, mouse; D014157:Transcription Factors