geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Splicing factor SRSF1 negatively regulates alternative splicing of MDM2 under damage


, : Splicing factor SRSF1 negatively regulates alternative splicing of MDM2 under damage. Nucleic Acids Research 43(8): 4202-4218

Genotoxic stress induces alternative splicing of the oncogene MDM2 generating MDM2-ALT1, an isoform attributed with tumorigenic properties. However, the mechanisms underlying this event remain unclear. Here we explore MDM2 splicing regulation by utilizing a novel minigene that mimics endogenous MDM2 splicing in response to UV and cisplatinum-induced DNA damage. We report that exon 11 is necessary and sufficient for the damage-specific alternative splicing of the MDM2 minigene and that the splicing factor SRSF1 binds exon 11 at evolutionarily conserved sites. Interestingly, mutations disrupting this interaction proved sufficient to abolish the stress-induced alternative splicing of the MDM2 minigene. Furthermore, SRSF1 overexpression promoted exclusion of exon 11, while its siRNA-mediated knockdown prevented the stress-induced alternative splicing of endogenous MDM2. Additionally, we observed elevated SRSF1 levels under stress and in tumors correlating with the expression of MDM2-ALT1. Notably, we demonstrate that MDM2-ALT1 splicing can be blocked by targeting SRSF1 sites on exon 11 using antisense oligonucleotides. These results present conclusive evidence supporting a negative role for SRSF1 in MDM2 alternative splicing. Importantly, we define for the first time, a clear-cut mechanism for the regulation of damage-induced MDM2 splicing and present potential strategies for manipulating MDM2 expression via splicing modulation.

US$19.90

PMID: 25845590

DOI: 10.1093/nar/gkv223


Other references

Barron, C.R.; Foxall, M.J.; Von Dollen, K.; Jones, P.A.; Shull, K.A., 1994: Marital status, social support, and loneliness in visually impaired elderly people. The purpose of this study was to investigate relationships between marital status, social support, and loneliness in visually impaired elderly people. The sample was derived from a larger study designed to examine loneliness in low-vision adults (...

Sargent, M., 1977: Co operative management: growth and development. Horticulture industry: 573

Melanson, E.L.; Dykstra, J.C.; Szuminsky, N., 2010: A novel approach for measuring energy expenditure in free-living humans. Measuring energy expenditure (EE) in free-living humans is difficult. In this study, we validated a novel instrument that measures free-living EE from direct calorimetry, i.e. the heat produced by the body. The sensor can be worn on the upper arm...

Hansen, M.A., 1972: Observations on 'direct reacting' plasma bilirubin in ruminants. The direct diazo (van den Bergh) reaction in bovine and ovine plasma was studied with different plasma diluents, of which a glycine buffer solution seemed the most suitable. The 'direct percentages', i.e. the values for 'direct reac...

Tsubura A.; Okada H.; Senzaki H.; Hatano T.; Morii S., 1991: Keratin expression in the normal breast and in breast carcinoma. The immunohistochemical reactivities of 69 cases of breast carcinoma were examined on methacarn-fixed, paraffin-embedded sections using eight different monoclonal antibodies which recognize one or a few keratin polypeptides. In the normal breast,...

Schulze, W.B.; Rodin, A.E., 1961: Anomalous origin of both coronary arteries. Report of a case with discussion of teratogenetic theories. A case of anomalous origin of both coronary arteries from the pulmonary artery is presented. It represents the 5th reported case, but only the 3rd with no other congenital anomalies aside from a patent ductus arteriosus. It is the only case in whi...

Barros, C.P.; Dieke, P.U.C., 2007: Analyzing the total productivity change in travel agencies. This article estimates changes in total productivity in travel agencies in two stages. In the first stage, it breaks down total productivity into technically efficient change and technological change by means of data envelopment analysis (DEA) app...

Kirchberg, S.; Fröhlich, R.; Studer, A., 2009: Stereoselective palladium-catalyzed carboaminoxylations of indoles with arylboronic acids and TEMPO. Indoles are not indolent: Various indoles react with arylboronic acids chemodivergently. C-H arylation of free indole and N-methylindole gives the corresponding C(2)-arylated indoles A whereas N-acylated, N-benzoylated, and N-Boc-protected indoles...

Yasui, M.; Narahara, K.; Kobayashi, M.; Iyoda, K.; Tanaka, H.; Makino, H.; Ohmiri, H.; Seino, Y., 1994: New familial nephropathy involving glomerular and tubular basement membranes. We describe two siblings, an 8-year-old boy and a 9-year-old girl, with severe mental retardation, dwarfism, optic atrophy and nephropathy. Laboratory examination showed beta-2-microglobulinuria, decreased creatinine clearance, hypercholesterolaem...

Kudo, N.; Oyamada, T.; Okutsu, M.; Kinoshita, M., 1996: Intermediate hosts of Gongylonema pulchrum Molin, 1857, in Aomori Prefecture, Japan. Between July 1987 and August 1988, a total of 16,422 dung beetles belonging to 13 species of 5 genera were collected from pastures in Rokkasho and Towada, Aomori Prefecture, Japan, and examined for 3rd-stage larvae of Gongylonema pulchrum. G. pulc...