Hoxa9 transduction induces hematopoietic stem and progenitor cell activity through direct down-regulation of geminin protein

• Published in: PloS one Vol. 8; no. 1; p. e53161
• Main Authors: Ohno, Yoshinori, Yasunaga, Shin'ichiro, Janmohamed, Salima, Ohtsubo, Motoaki, Saeki, Keita, Kurogi, Toshiaki, Mihara, Keichiro, Iscove, Norman N, Takihara, Yoshihiro
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.01.2013; Public Library of Science (PLoS)
• Subjects: Animals; Biology; Biophysics; Blood; Cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Colony-Forming Units Assay - methods; Cullin Proteins - genetics; Cullin Proteins - metabolism; Deoxyribonucleic acid; Derivatives; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Geminin; Gene expression; Genes; Genetic aspects; HEK293 Cells; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; HOX gene; HOXB4 protein; Humans; Immunoblotting; Immunology; Leukemia; Leukemogenesis; Licenses; Ligases; Medical prognosis; Medicine; Mice; Mice, Inbred C57BL; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Progenitor cells; Protein Binding; Proteins; Regulators; Retroviridae - genetics; RNA Interference; Rodents; Sf9 Cells; siRNA; Stem cells; Transcription; Transcription (Genetics); Transduction, Genetic; Translocation; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053161

Hoxb4, a 3'-located Hox gene, enhances hematopoietic stem cell (HSC) activity, while a subset of 5'-located Hox genes is involved in hematopoiesis and leukemogenesis, and some of them are common translocation partners for Nucleoporin 98 (Nup98) in patients with leukemia. Although these Hox gene derivatives are believed to act as transcription regulators, the molecular involvement of the Hox gene derivatives in hematopoiesis and leukemogenesis remains largely elusive. Since we previously showed that Hoxb4 forms a complex with a Roc1-Ddb1-Cul4a ubiquitin ligase core component and functions as an E3 ubiquitin ligase activator for Geminin, we here examined the E3 ubiquitin ligase activities of the 5'-located Hox genes, Hoxa9 and Hoxc13, and Nup98-Hoxa9. Hoxa9 formed a similar complex with the Roc1-Ddb1-Cul4a component to induce ubiquitination of Geminin, but the others did not. Retroviral transduction-mediated overexpression or siRNA-mediated knock-down of Hoxa9 respectively down-regulated or up-regulated Geminin in hematopoietic cells. And Hoxa9 transduction-induced repopulating and clonogenic activities were suppressed by Geminin supertransduction. These findings suggest that Hoxa9 and Hoxb4 differ from Hoxc13 and Nup98-Hoxa9 in their molecular role in hematopoiesis, and that Hoxa9 induces the activity of HSCs and hematopoietic progenitors at least in part through direct down-regulation of Geminin.