Abstract

   Arginylation is an emerging posttranslational modification mediated
   by  arginyltransferase  (ATE1)  that  is  essential  for  mammalian
   embryogenesis  and  regulation  of  the   cytoskeleton.   Here,  we
   discovered  that  Ate1   knockout   embryonic  fibroblasts  exhibit
   tumorigenic     properties,      including     abnormally     rapid
   contact-independent  growth,  reduced  ability  to  form  cell-cell
   contacts, and chromosomal  aberrations.   Ate1 knockout fibroblasts
   can form large colonies in Matrigel and  exhibit invasive behavior,
   unlike wild  type  fibroblasts.   Furthermore,  Ate1 knockout cells
   form tumors in subcutaneous  xenograft  assays in immunocompromised
   mice.  Abnormal growth in these cells can  be  partially rescued by
   reintroduction of stably  expressed  specific  Ate1 isoforms, which
   also reduce the ability of these cells to form tumors.  Tumor array
   studies   and   bioinformatics   analysis   show   that   Ate1   is
   down-regulated in several  types  of  human  cancer  samples at the
   protein  level,  and   that   its   transcription  level  inversely
   correlates with metastatic  progression  and  patient survival.  We
   conclude that Ate1 knockout results  in carcinogenic transformation
   of  cultured  fibroblasts,  suggesting  that  in  addition  to  its
   previously  known  activities  Ate1  gene  is  essential for  tumor
   suppression  and  also  likely   participates   in  suppression  of
   metastatic growth.

   (Oncogene, doi:10.1038/onc.2015.473, 2015)