title: Stable form of JAB1 enhances proliferation and maintenance of hematopoietic progenitors.
abstract: Overexpression of JAB1 is observed in a variety of human cancers, but how JAB1 is involved in tumor development remained to be investigated. Here we analyzed mice with modified Jab1 expression. Mice ectopically expressing a more stable form of JAB1 protein under the control of a constitutive promoter were rescued from the embryonic lethality caused by the Jab1(-/-) allele and developed a myeloproliferative disorder in a gene dosage-dependent manner. Hematopoietic cells from the bone marrow of Jab1 transgenic mice had a significantly larger stem cell population and exhibited higher and transplantable proliferative potential. In contrast, Jab1(+/-) mice, which express approximately 70% as much JAB1 protein as their wild-type littermates, showed inefficient hematopoiesis. Expression of the tumor suppressor p16(INK4a) was inversely correlated with that of JAB1, and the oncoprotein SMYD3, a newly identified JAB1 interactor, suppressed transcription of p16 in cooperation with JAB1. Thus, the expression and function of JAB1 are critical for the proliferation and maintenance of hematopoietic progenitors.
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoneda-Kato
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoshida
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Kato
mesh_terms: D000483:Alleles; D000818:Animals; D000075686:COP9 Signalosome Complex; D019556:COS Cells; D002522:Chlorocebus aethiops; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D047908:Intracellular Signaling Peptides and Proteins; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex