title: A new function of the splicing factor SRSF2 in the control of E2F1-mediated cell cycle progression in neuroendocrine lung tumors.
abstract: The transcription factor E2F1 belongs to the E2F family and plays a crucial role during cell cycle progression and apoptosis. Ser/Arg-Rich (SR) proteins are a family of RNA-binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing events. We previously identified the SR protein SRSF2 as a new transcriptional target of E2F1 and demonstrated that both proteins cooperate to induce apoptosis in non-small cell lung carcinoma. In this study, we postulated that SRSF2 is also involved in the proliferative functions of E2F1. Using IHC, we first demonstrate that SRSF2 and its phosphorylated form (P-SRSF2) are overexpressed in neuroendocrine lung tumors that are highly proliferative tumors expressing high levels of E2F1. Importantly, we show a direct correlation between cyclin E, an E2F1-target gene controlling S phase, and P-SRSF2 proteins levels (p = 0.0083), suggesting a role of SRSF2 in E2F1-mediated cellular proliferation. Accordingly, using neuroendocrine lung carcinoma cell lines, we demonstrate that SRSF2 is a cell cycle-regulated protein involved in entry and progression into S phase. We also provide evidence that SRSF2 interacts with E2F1 and stimulates its transcriptional control of cell cycle target genes such as cyclin E. Finally, we show that inhibition of AKT signaling pathway prevents SRSF2 phosphorylation and activity toward E2F1 transcriptional function. Taken together, these results identify a new role of SRSF2 in the control of cell cycle progression and reinforce the functional link between SRSF2 and E2F1 proteins.
authors.affiliation: INSERM, U823, Equipe 2 Bases Moléculaires de la Progression des Cancers du Poumon, Grenoble, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Edmond
authors.forename: Galina
authors.initials: G
authors.lastname: Merdzhanova
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gout
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gazzeri
authors.forename: Beatrice
authors.initials: B
authors.lastname: Eymin
mesh_terms: D015153:Blotting, Western; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D008175:Lung Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000378:metabolism*; D016196:S Phase / Q000502:physiology*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019927:Cyclin E; D017931:DNA Primers; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D008156:Luciferases
keywords: AKT; E2F1; SRSF2; cellular proliferation; neuroendocrine lung tumors; p45SKP2