Wilms' tumor 1-associating protein regulates G2/M transition through stabilization of cyclin A2 mRNA.
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.
Horiuchi
Keiko
K
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Meguro, Tokyo 153-8904, Japan.
Umetani
Michihisa
M
Minami
Takashi
T
Okayama
Hiroto
H
Takada
Shinji
S
Yamamoto
Masayuki
M
Aburatani
Hiroyuki
H
Reid
Patrick C
PC
Housman
David E
DE
Hamakubo
Takao
T
Kodama
Tatsuhiko
T
D020413:3' Untranslated Regions / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002455:Cell Division; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D019925:Cyclin A / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D016195:G2 Phase; D005838:Genotype; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
D020413:3' Untranslated Regions; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C419554:WTAP protein, human; C486008:Wtap protein, mouse