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miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis.

Authors
Beezhold-K; Liu-J; Kan-H; Meighan-T; Castranova-V; Shi-X; Chen-F
Source
Toxicol Sci 2011 Jul; 123(2):411-420
NIOSHTIC No.
20039821
Abstract
The role of trivalent arsenic (As3+) on the regulation of the recently identified noncoding small RNAs, mainly microRNAs, has not been explored so far. In the present study, we provide evidence showing that As3+ is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As3+ is concentration dependent and associated with the expression of the host gene of miR-190, talin 2, a gene encoding a high-molecular-weight cytoskeletal protein. The elevated level of miR-190 induced by As3+ is capable of downregulating the translation of the PH domain leucine-rich repeat protein phosphatase (PHLPP), a negative regulator of Akt signaling. Such a downregulation is occurred through direct interaction of the miR-190 with the 3'-UTR region of the PHLPP mRNA, leading to a diminished PHLPP protein expression and consequently, an enhanced Akt activation and expression of vascular endothelial growth factor, an Akt-regulated protein. Overexpression of miR-190 itself is able to enhance proliferation and malignant transformation of the cells as determined by anchorage-independent growth of the cells in soft agar. Accordingly, the data presented suggest that induction of miR-190 is one of the key mechanisms in As3+ -induced carcinogenesis.
Keywords
Biological-effects; Biological-factors; Carcinogenesis; Cell-biology; Cellular-reactions; Cytology; Genotoxic-effects; Pulmonary-disorders; Pulmonary-system; Pulmonary-system-disorders; Respiratory-system-disorders; Statistical-analysis; Author Keywords: arsenite; microRNA; Akt; carcinogenesis
Contact
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201
CODEN
TOSCF2
CAS No.
7440-38-2
Publication Date
20110712
Document Type
Journal Article
Email Address
fchen@wayne.edu
Fiscal Year
2011
NTIS Accession No.
NTIS Price
Identifying No.
B11122011
Issue of Publication
2
ISSN
1096-6080
NIOSH Division
HELD
Priority Area
Manufacturing; Mining
Source Name
Toxicological Sciences
State
WV; MI; KY
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