Stable form of JAB1 enhances proliferation and maintenance of hematopoietic progenitors.
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.
Mori
Masaaki
M
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
Yoneda-Kato
Noriko
N
Yoshida
Akihiro
A
Kato
Jun-ya
JY
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*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D047908:Intracellular Signaling Peptides and Proteins; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex