Wilms' tumor 1-associating protein regulates G2/M transition through stabilization of cyclin A2 mRNA

Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17278-83. doi: 10.1073/pnas.0608357103. Epub 2006 Nov 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adenoviridae / genetics
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins
  • Cell Division*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cyclin A / genetics*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / metabolism
  • G2 Phase*
  • Genotype
  • Humans
  • Mice
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • RNA Splicing Factors
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics

Substances

  • 3' Untranslated Regions
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin A
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA, Small Interfering
  • WTAP protein, human
  • Wtap protein, mouse

Associated data

  • GEO/GSE2327