دورية أكاديمية
CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis.
| العنوان: | CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis. |
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| المؤلفون: | Kim JH; Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037., Hedrick S; Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037., Tsai WW; Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037., Wiater E; Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037., Le Lay J; Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Kaestner KH; Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Leblanc M; Gene Expression Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037., Loar A; STAT Veterinary Lab, San Diego, CA 92121., Montminy M; Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037; montminy@salk.edu. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Oct 31; Vol. 114 (44), pp. 11739-11744. Date of Electronic Publication: 2017 Oct 16. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Bone Marrow/*physiology , Cyclic AMP Response Element-Binding Protein/*metabolism , Hematopoiesis/*physiology , Transcription Factors/*metabolism, Animals ; Bone Marrow Transplantation ; Embryonic Development ; Gene Expression Regulation, Developmental/physiology ; Granulocyte Colony-Stimulating Factor/metabolism ; Janus Kinases/genetics ; Janus Kinases/metabolism ; Mice ; Mice, Knockout ; NF-kappa B/genetics ; NF-kappa B/metabolism ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Transcription Factors/genetics |
| مستخلص: | Populations of circulating immune cells are maintained in equilibrium through signals that enhance the retention or egress of hematopoietic stem cells (HSCs) from bone marrow (BM). Prostaglandin E2 (PGE2) stimulates HSC renewal and engraftment through, for example, induction of the cAMP pathway. Triggering of PGE2 receptors increases HSC survival in part via the PKA-mediated induction of the cAMP response element-binding protein (CREB) signaling pathway. PKA stimulates cellular gene expression by phosphorylating CREB at Ser133 and by promoting the dephosphorylation of the cAMP- responsive transcriptional coactivators (CRTCs). We show here that disruption of both CRTC2 and CRTC3 causes embryonic lethality, and that a single allele of either CRTC2 or CRTC3 is sufficient for viability. CRTC2 knockout mice that express one CRTC3 allele (CRTC2/3m mice) develop neutrophilia and splenomegaly in adulthood due to the up-regulation of granulocyte-colony stimulating factor (G-CSF); these effects are reversed following administration of neutralizing anti-G-CSF antiserum. Adoptive transfer of CRTC2/3m BM conferred the splenomegaly/neutrophilia phenotype in WT recipients. Targeted disruption of both CRTC2 and CRTC3 in stromal cells with a mesenchymal Prx1-Cre transgene also promoted this phenotype. Depletion of CRTC2/3 was found to decrease the expression of Suppressor of Cytokine Signaling 3 (SOCS3), leading to increases in STAT3 phosphorylation and to the induction of CEBPβ, a key regulator of the G-CSF gene. As small molecule inhibition of JAK activity disrupted CEBPβ induction and reduced G-CSF expression in CRTC2/3m stromal cells, our results demonstrate how cross-coupling between the CREB/CRTC and JAK/STAT pathways contributes to BM homeostasis. Competing Interests: Conflict of interest statement: J.-H.K., W.-W.T., and A.L. are currently employed at commercial entities with scientific interest in related areas of investigation. (Published under the PNAS license.) |
| References: | Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15642-7. (PMID: 26644581) Immunity. 2004 Feb;20(2):153-65. (PMID: 14975238) J Exp Med. 2015 May 4;212(5):633-48. (PMID: 25870201) Blood. 2008 Feb 15;111(4):1767-72. (PMID: 18057230) N Engl J Med. 2012 Mar 1;366(9):787-98. (PMID: 22375970) Genesis. 2002 Jun;33(2):77-80. (PMID: 12112875) Nat Med. 2005 Feb;11(2):191-8. (PMID: 15685170) CSH Protoc. 2008 Dec 01;2008:pdb.prot5080. (PMID: 21356739) J Exp Med. 2015 May 4;212(5):665-80. (PMID: 25870199) Cell Rep. 2015 Feb 24;10(7):1149-57. (PMID: 25704817) Nat Rev Mol Cell Biol. 2011 Mar;12(3):141-51. (PMID: 21346730) J Clin Invest. 2013 Oct;123(10):4318-28. (PMID: 24051374) Blood. 2010 Oct 7;116(14):2462-71. (PMID: 20581311) Blood. 2002 Jul 15;100(2):467-73. (PMID: 12091337) Differentiation. 2011 Apr;81(4):222-32. (PMID: 21396766) J Biol Chem. 2002 Nov 15;277(46):44147-54. (PMID: 12215436) Cell. 1995 Jan 27;80(2):353-61. (PMID: 7530603) Nat Cell Biol. 2008 Aug;10(8):1003-11. (PMID: 18641637) J Exp Med. 2015 May 4;212(5):649-63. (PMID: 25870200) Stem Cells. 1994 Jul;12(4):416-23. (PMID: 7524894) Nature. 2007 Jun 21;447(7147):1007-11. (PMID: 17581586) Gene. 2016 Jun 10;584(1):97-109. (PMID: 26968890) Nature. 2010 Dec 16;468(7326):933-9. (PMID: 21164481) Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3087-92. (PMID: 20133702) Ann Hematol. 2003 Apr;82(4):207-13. (PMID: 12707722) Blood. 1994 May 1;83(9):2469-79. (PMID: 7513199) |
| معلومات مُعتمدة: | P01 DK049210 United States DK NIDDK NIH HHS; R37 DK083834 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: C/EBPβ; CREB; CRTC; G-CSF; cAMP |
| المشرفين على المادة: | 0 (CRTC3 protein, mouse) 0 (Crtc2 protein, mouse) 0 (Cyclic AMP Response Element-Binding Protein) 0 (NF-kappa B) 0 (STAT3 Transcription Factor) 0 (Stat3 protein, mouse) 0 (Transcription Factors) 143011-72-7 (Granulocyte Colony-Stimulating Factor) EC 2.7.10.2 (Janus Kinases) |
| تواريخ الأحداث: | Date Created: 20171029 Date Completed: 20180619 Latest Revision: 20190808 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC5676928 |
| DOI: | 10.1073/pnas.1712616114 |
| PMID: | 29078378 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1712616114 |