title: hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNP L.
abstract: Caspase-9 has two splice variants, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b, which are regulated by RNA trans-factors associated with exon 3 of caspase-9 pre-mRNA (C9/E3). In this study, we identified hnRNP U as an RNA trans-factor associated with C9/E3. Down-regulation of hnRNP U led to a decrease in the caspase-9a/9b mRNA ratio, demonstrating a novel enhancing function. Importantly, hnRNP U bound specifically to C9/E3 at an RNA cis-element previously reported as the binding site for the splicing repressor, hnRNP L. Phosphorylated hnRNP L interfered with hnRNP U binding to C9/E3, and our results demonstrate the importance of the phosphoinositide 3-kinase/AKT pathway in modulating the association of hnRNP U to C9/E3. Taken together, these findings show that hnRNP U competes with hnRNP L for binding to C9/E3 to enhance the inclusion of the four-exon cassette, and this splice-enhancing function is blocked by the AKT pathway via phosphorylation of hnRNP L.
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298; Vietnam Education Foundation, Arlington, Virginia 22201.
authors: Ngoc T
authors: NT
authors: Vu
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Margaret A
authors: MA
authors: Park
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Jacqueline C
authors: JC
authors: Shultz
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Rachel W
authors: RW
authors: Goehe
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: L Alexis
authors: LA
authors: Hoeferlin
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Michael D
authors: MD
authors: Shultz
authors: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors: Sarah A
authors: SA
authors: Smith
authors: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors: Kristen W
authors: KW
authors: Lynch
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298; Research and Development, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249; The Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298. Electronic address: cechalfant@vcu.edu.
authors: Charles E
authors: CE
authors: Chalfant
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D001665:Binding Sites; D053453:Caspase 9 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005091:Exons; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000378:metabolism*; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D007527:Isoenzymes; D012322:RNA Precursors; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; C506433:CASP9 protein, human; D053453:Caspase 9
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