Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer.
SR and hnRNP proteins were initially discovered as regulators of alternative splicing: the process of controlled removal of introns and selective joining of exons through which multiple transcripts and, subsequently, proteins can be expressed from a single gene. Alternative splicing affects genes involved in all crucial cellular processes, including apoptosis. During cancerogenesis impaired apoptotic control facilitates survival of cells bearing molecular aberrations, contributing to their unrestricted proliferation and chemoresistance. Apparently, SR and hnRNP proteins regulate all levels of expression of apoptotic genes, including transcription initiation and elongation, alternative splicing, mRNA stability, translation, and protein degradation. The frequently disturbed expressions of SR/hnRNP proteins in cancers lead to impaired functioning of target apoptotic genes, including regulators of the extrinsic (Fas, caspase-8, caspase-2, c-FLIP) and the intrinsic pathway (Apaf-1, caspase-9, ICAD), genes encoding Bcl-2 proteins, IAPs, and p53 tumor suppressor. Prototypical members of SR/hnRNP families, SRSF1 and hnRNP A1, promote synthesis of anti-apoptotic splice variants of Bcl-x and Mcl-1, which results in attenuation of programmed cell death in breast cancer and chronic myeloid leukemia. SR/hnRNP proteins significantly affect responses to chemotherapy, acting as mediators or modulators of drug-induced apoptosis. Aberrant expression of SRSF1 and hnRNP K can interfere with tumor responses to chemotherapy in pancreatic and liver cancers. Currently, a number of splicing factor inhibitors is being tested in pre-clinical and clinical trials. In this review we discuss recent findings on the role of SR and hnRNP proteins in apoptotic control in cancer cells as well as their significance in anticancer treatments.
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland.
Hanna
H
Kędzierska
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland. Electronic address: apiekielko@cmkp.edu.pl.
Agnieszka
A
Piekiełko-Witkowska
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D022821:RNA Splice Sites / Q000502:physiology; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000378:metabolism
D034441:Heterogeneous-Nuclear Ribonucleoproteins; D022821:RNA Splice Sites; D000072260:RNA Splicing Factors; D020169:Caspases
Apoptosis; Cancer; Caspase; SRSF1; SRSF2; Splicing factor