title: Paired-like homeodomain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation.
abstract: The eukaryotic cell cycle is regulated by sequential activation and inactivation of cyclin-cyclin-dependent kinase (Cdk) complexes. In this work, we screened human cDNAs that can rescue yeast Saccharomyces cerevisiae from lethality caused by ectopic expression of human cyclin E and isolated a cDNA encoding ESXR1, a paired-like homeodomain-containing protein with a unique C-terminal proline-rich repeat region. In adult tissues, ESXR1 is primarily expressed in the testis. We demonstrate that ESXR1 prevents degradation of ubiquitinated cyclins in human cells. Accordingly, elevation of ESXR1 level results in accumulation of cyclin A and cyclin B1 and thereby provokes M-phase arrest. In human cells, the 65-kDa full-length ESXR1 protein is capable of proteolytically processing into N-terminal 45-kDa and C-terminal 20-kDa fragments. The C-terminal fragment, containing a proline-rich repeat region, is localized to the cytoplasm and displays the ability to inhibit cyclin degradation. In contrast, the N-terminal fragment, containing a paired-like homeodomain, is localized exclusively in the nucleus, suggesting that it plays a role in transcription. Our results indicate that proteolytic processing of ESXR1 plays a role in concerted regulation of the cell cycle and transcription in human cells.
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine and Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Heita
authors.initials: H
authors.lastname: Ozawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ashizawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Naito
authors.forename: Masatomo
authors.initials: M
authors.lastname: Yanagihara
authors.forename: Naomi
authors.initials: N
authors.lastname: Ohnishi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maeda
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Jo
authors.forename: Hideaki
authors.initials: H
authors.lastname: Higashi
authors.forename: Akira
authors.initials: A
authors.lastname: Kakita
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016213:Cyclins / Q000378:metabolism*; D017931:DNA Primers; D018076:DNA, Complementary; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016213:Cyclins; D017931:DNA Primers; D018076:DNA, Complementary; C432969:ESX1 protein, human; D018398:Homeodomain Proteins