title: Regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice by PSF protein and a VL30 noncoding RNA.
abstract: 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-oncogene Rab23, repressing transcription, and VL30-1 RNA binds and releases PSF from Rab23, 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 a trans effect rather than a cis 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.
authors.affiliation: Center for Functional Genomics and Bioinformatics, College of Life Science, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.forename: Guangfeng
authors.initials: G
authors.lastname: Zhang
authors.forename: Alan
authors.initials: A
authors.lastname: Garen
authors.forename: Xu
authors.initials: X
authors.lastname: Song
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D000072670:PTB-Associated Splicing Factor; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018626:Retroelements; D014158:Transcription, Genetic; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D000072670:PTB-Associated Splicing Factor; D000090063:Proto-Oncogene Mas; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; D018626:Retroelements; D012313:RNA; C431746:Rab23 protein, mouse; D020691:rab GTP-Binding Proteins