title: Human HTm4 is a hematopoietic cell cycle regulator.
abstract: Proper control of cell cycle progression is critical for the constant self-renewal, differentiation, and homeostasis of the hematopoietic system. Cells of all types share the common cell cycle regulators. The different expression patterns of common regulators, in a broad sense, define cell-type or lineage specificity. However, there remains the possibility of hematopoietic cell cycle regulators tailored to the demands of the hematopoietic system. Here we describe a novel protein, HTm4, which serves as a hematopoietic cell cycle regulator. Our data indicate that HTm4 is expressed in hematopoietic tissues and is tightly regulated during the differentiation of hematopoietic stem cells. It binds to cyclin-dependent kinase-associated (CDK-associated) phosphatase-CDK2 (KAP-CDK2) complexes, and the three proteins demonstrate similar patterns of cellular expression in human lymphoid tissues. HTm4 stimulates the phosphatase activity of KAP, and its C-terminal region is required for binding to KAP-CDK2 complexes and the modulation of KAP activity. Overexpression of HTm4 can cause cell cycle arrest at the G(0)/G(1) phase. Thus, HTm4 is a novel hematopoietic modulator for the G(1)-S cell cycle transition.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: José L
authors.initials: JL
authors.lastname: Donato
authors.forename: Jon
authors.initials: J
authors.lastname: Ko
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Taro
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Xiao-Quan
authors.initials: XQ
authors.lastname: Mao
authors.forename: David
authors.initials: D
authors.lastname: Beach
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Chaker N
authors.initials: CN
authors.lastname: Adra
mesh_terms: D000595:Amino Acid Sequence; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D054637:Dual-Specificity Phosphatases; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C089821:MS4A3 protein, human; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C084429:CDKN3 protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases