title: TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC.
abstract: Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110(nrb)/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34(+) cells and decreased with differentiation of CD34(+) cells. TIP110 mRNA was also expressed in phenotyped mouse marrow hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Using TIP110 transgenic (TIP110(TG)) and haploinsufficient (TIP110(+/-)) mice, we found that increased TIP110 expression enhanced HPC numbers, survival, and cell cycling, whereas decreased TIP110 expression had the opposite effects. Moreover, TIP110(+/-) bone marrow HPCs responded more effectively, and TIP110(TG) HPCs less effectively, than those of wild-type control mice to recovery from the cell-cycle-active drug 5-fluorouracil (5-FU). Unexplained sex differences were noted in HSC competitive repopulating ability, but not HPC numbers, in TIP110(TG) mice. Intracellularly, TIP110 regulated CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulated the expression of each other. These results demonstrate a role for TIP110 in the regulation of hematopoiesis, effects that are likely linked to TIP110 regulation of CMYC.
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. yliu2@iupui.edu
authors: Ying
authors: Y
authors: Liu
authors: Khalid
authors: K
authors: Timani
authors: Charlie
authors: C
authors: Mantel
authors: Yan
authors: Y
authors: Fan
authors: Giao
authors: G
authors: Hangoc
authors: Scott
authors: S
authors: Cooper
authors: Johnny J
authors: JJ
authors: He
authors: Hal E
authors: HE
authors: Broxmeyer
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C416530:SART3 protein, human; D005472:Fluorouracil