Article ; Online: miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis.
Toxicological sciences : an official journal of the Society of Toxicology
2011 Volume 123, Issue 2, Page(s) 411–420
Abstract: The role of trivalent arsenic (As(3+)) 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 As(3+) is a potent inducer for the expression ...
| Abstract | The role of trivalent arsenic (As(3+)) 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 As(3+) is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As(3+) 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 As(3+) 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 As(3+)-induced carcinogenesis. |
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| MeSH term(s) | Arsenic Poisoning ; Arsenic Trioxide ; Arsenicals ; Bronchi/drug effects ; Bronchi/pathology ; Carcinogens, Environmental/toxicity ; Cell Line ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/chemically induced ; Down-Regulation/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Gene Expression Regulation/drug effects ; Gene Silencing ; Humans ; MicroRNAs/biosynthesis ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Oxides/toxicity ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; RNA, Messenger/metabolism ; Talin/genetics ; Talin/metabolism |
| Chemical Substances | Arsenicals ; Carcinogens, Environmental ; MicroRNAs ; Nuclear Proteins ; Oxides ; RNA, Messenger ; TLN2 protein, human ; Talin ; PHLPP1 protein, human (EC 3.1.3.16) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Arsenic Trioxide (S7V92P67HO) |
| Language | English |
| Publishing date | 2011-07-12 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 1420885-4 |
| ISSN | 1096-0929 ; 1096-6080 |
| ISSN (online) | 1096-0929 |
| ISSN | 1096-6080 |
| DOI | 10.1093/toxsci/kfr188 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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