Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis.
The product of the Snail1 gene is a transcriptional repressor required for triggering the epithelial-to-mesenchymal transition. Furthermore, ectopic expression of Snail1 in epithelial cells promotes resistance to apoptosis. In this study, we demonstrate that this resistance to gamma radiation-induced apoptosis caused by Snail1 is associated with the inhibition of PTEN phosphatase. In MDCK cells, mRNA levels of the p53 target gene PTEN are induced after gamma radiation; the transfection of Snail1 prevents this up-regulation. Decreased mRNA levels of PTEN were also detected in RWP-1 cells after the ectopic expression of this transcriptional factor. Snail1 represses and associates to the PTEN promoter as detected both by the electrophoretic mobility shift assay and chromatin immunoprecipitation experiments performed with either endogenous or ectopic Snail1. The binding of Snail1 to the PTEN promoter increases after gamma radiation, correlating with the stabilization of Snail1 protein, and prevents the association of p53 to the PTEN promoter. These results stress the critical role of Snail1 in the control of apoptosis and demonstrate the regulation of PTEN phosphatase by this transcriptional repressor.
Escrivà
Maria
M
Institut Municipal d'Investigació Mèdica, Parc de Recerca Biomèdica de Barcelona, c/Dr. Aiguader 88, E-08003 Barcelona, Spain.
Peiró
Sandra
S
Herranz
Nicolás
N
Villagrasa
Patricia
P
Dave
Natàlia
N
Montserrat-Sentís
Bàrbara
B
Murray
Stephen A
SA
Francí
Clara
C
Gridley
Thomas
T
Virtanen
Ismo
I
García de Herreros
Antonio
A
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D018076:DNA, Complementary; D004285:Dogs; D016195:G2 Phase; D005720:Gamma Rays; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D049409:Luciferases, Firefly / Q000032:analysis / Q000378:metabolism; D049410:Luciferases, Renilla / Q000032:analysis / Q000378:metabolism; D049408:Luminescent Agents / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000473:pathology; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012641:Selection, Genetic; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
D018076:DNA, Complementary; D049408:Luminescent Agents; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D011691:Puromycin; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase