Wilms' Tumor 1-Associating Protein Regulates G₂/M Transition through Stabilization of Cyclin A2 MRNA

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 46; pp. 17278 - 17283
• Main Authors: Horiuchi, Keiko, Umetani, Michihisa, Minami, Takashi, Okayama, Hiroto, Takada, Shinji, Yamamoto, Masayuki, Aburatani, Hiroyuki, Reid, Patrick C., Housman, David E., Hamakubo, Takao, Kodama, Tatsuhiko
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.11.2006; National Acad Sciences
• Subjects: 3' Untranslated Regions - genetics; Adenoviridae - genetics; Animals; Biological Sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell cycle; Cell Division; Cells, Cultured; Cercopithecus aethiops; Cyclin A - genetics; Cyclins; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryos; G2 Phase; Gene expression regulation; Genotype; Human umbilical vein endothelial cells; Humans; Messenger RNA; Mice; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Binding; Protein synthesis; RNA stability; RNA, Messenger - genetics; RNA, Small Interfering - genetics; RNA-protein interactions; Small interfering RNA; Studies; Three prime untranslated regions; Transfection; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0608357103

Wilms' tumor 1-associating protein (WTAP) has been reported to be a ubiquitously expressed nuclear protein. Although a relation to splicing factors has been postulated, its actual physiological function still remains to be elucidated. To investigate the role of WTAP, we generated WTAP-knockout mice and performed small interfering RNA (siRNA)-mediated knockdown analyses in primary cultured cells. In DNA microarrays using human umbilical vein endothelial cells, WTAP-targeted siRNA treatment resulted in markedly reduced expression of cell-cycle-related genes. siRNA-mediated WTAP knockdown down-regulated the stability of cyclin A2 mRNA through a nine-nucleotide essential sequence in cyclin A2 mRNA 3' UTR. WTAP knockdown induced G2 accumulation, which is partially rescued by adenoviral overexpression of cyclin A2. Moreover, WTAP-null mice exhibited proliferative failure with death resulting at approximately embryonic day 6.5, an etiology almost identical to cyclin A2-null mice. Collectively, these findings establish WTAP as an essential factor for the stabilization of cyclin A2 mRNA, thereby regulating G₂/M cell-cycle transition.