Open AccessRegulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice by PSF protein and a VL30 noncoding RNA
Author(s) -
Gang Wang,
Ying Cui,
Guangfeng Zhang,
Alan Garen,
Shumin Xu
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0909022106
Subject(s) - rna , carcinogenesis , microbiology and biotechnology , transcription (linguistics) , biology , gene expression , small hairpin rna , oncogene , small interfering rna , antisense rna , cancer research , gene , cell cycle , genetics , linguistics , philosophy
We describe the role of PSF protein and VL30–1 RNA, a mouse retroelement noncoding RNA, in the reversible regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice. The experiments involved increasing expression of PSF or VL30–1 RNA in NIH/3T3 fibroblast cells and B16F10 melanoma cells by transfecting the respective coding genes under control of a strong promoter or decreasing expression by transfecting a shRNA construct that causes degradation of PSF mRNA or VL30–1 RNA. The results are as follows: (i ) PSF binds to the proto-oncogeneRab23 , repressing transcription, and VL30–1 RNA binds and releases PSF fromRab23 , activating transcription; (ii ) increasing expression of PSF or decreasing expression of VL30–1 RNA suppresses cell proliferation in culture and tumorigenesis in mice; and (iii ) decreasing expression of PSF or increasing expression of VL30–1 RNA promotes cell proliferation in culture and tumorigenesis in mice. These results indicate that PSF is a major tumor-suppressor protein and VL30–1 RNA is a major tumor-promoter RNA in mice. Although VL30–1 RNA can integrate into the cell genome, tumor promotion by VL30–1 RNA involves atrans effect rather than acis effect on gene transcription. Expression of VL30–1 RNA is 5- to 8-fold higher in mouse tumor lines than in mouse fibroblast or myoblast lines, whereas expression of PSF mRNA does not decrease in the tumor lines, suggesting that tumorigenesis is driven by an increase of VL30–1 RNA rather than a decrease of PSF. A similar regulatory mechanism functions in human cells, except that human PSF-binding RNAs replace VL30–1 RNA, which is not encoded in the human genome. We propose that PSF protein and PSF-binding RNAs have a central role in the reversible regulation of mammalian cell proliferation and tumorigenesis and that increasing PSF expression or decreasing PSF-binding RNA expression in tumor cells is a potential therapeutic strategy for cancer.