Nucleolin links to arsenic-induced stabilization of GADD45alpha mRNA.
The present study shows that arsenic induces GADD45alpha (growth arrest and DNA damage inducible gene 45alpha) mainly through post-transcriptional mechanism. Treatment of the human bronchial epithelial cell line, BEAS-2B, with arsenic(III) chloride (As3+) resulted in a significant increase in GADD45alpha protein and mRNA. However, As3+ only exhibited a marginal effect on the transcription of the GADD45alpha gene. The accumulation of GADD45alpha mRNA is largely achieved by the stabilization of GADD45alpha mRNA in the cellular response to As3+. As3+ is able to induce binding of mRNA stabilizing proteins, nucleolin and less potently, HuR, to the GADD45alpha mRNA. Although As3+ was unable to affect the expression of nucleolin, treatment of the cells with As3+ resulted in re-distribution of nucleolin from nucleoli to nucleoplasm. Silencing of the nucleolin mRNA by RNA interference reversed As3+-induced stabilization of the GADD45alpha mRNA and accumulation of the GADD45alpha protein. Stabilization of GADD45alpha mRNA, thus, represents a novel mechanism contributing to the production of GADD45alpha and cell cycle arrest in response to As3+.
Zhang
Yadong
Y
Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Bhatia
Deepak
D
Xia
Hongfeng
H
Castranova
Vince
V
Shi
Xianglin
X
Chen
Fei
F
D001152:Arsenicals / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002712:Chlorides / Q000494:pharmacology*; D020868:Gene Silencing; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000097796:Nucleolin; D000097642:GADD45 Proteins
D001152:Arsenicals; D018797:Cell Cycle Proteins; D002712:Chlorides; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C050510:arsenic trichloride