Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer.

Proceedings of the National Academy of Sciences of the United States of America
Gabriel SanchezMartin Dutertre

Abstract

Pre-mRNA splicing and polyadenylation are tightly connected to transcription, and transcriptional stimuli and elongation dynamics can affect mRNA maturation. However, whether this regulatory mechanism has a physio/pathological impact is not known. In cancer, where splice variant expression is often deregulated, many mutated oncogenes are transcriptional regulators. In particular, the Ewing sarcoma (EwSa) oncogene, resulting from a fusion of the EWS and FLI1 genes, encodes a well characterized transcription factor. EWS-FLI1 directly stimulates transcription of the CCND1 protooncogene encoding cyclin D1a and a less abundant but more oncogenic splice isoform, D1b. We show that, although both EWS and EWS-FLI1 enhance cyclin D1 gene expression, they regulate the D1b/D1a transcript ratio in an opposite manner. Detailed analyses of RNA polymerase dynamics along the gene and of the effects of an inhibitor of elongation show that EWS-FLI1 favors D1b isoform expression by decreasing the elongation rate, whereas EWS has opposite effects. As a result, the D1b/D1a ratio is elevated in EwSa cell lines and tumors. The endogenous D1b protein is enriched in nuclei, where the oncogenic activity of cyclin D1 is known to occur, and depleting D1b i...Continue Reading

References

Oct 23, 1997·Proceedings of the National Academy of Sciences of the United States of America·P CramerA R Kornblihtt
May 4, 1999·International Journal of Cancer. Journal International Du Cancer·Y HosokawaM Seto
Apr 13, 2001·The Journal of Biological Chemistry·L L Knoop, S J Baker
Apr 5, 2002·Trends in Genetics : TIG·Javier F Cáceres, Alberto R Kornblihtt
Jul 9, 2002·Molecular and Cellular Biology·Martha L PetersonFrankie Davis
Sep 11, 2002·The Journal of Biological Chemistry·Guadalupe NoguesAlberto R Kornblihtt
May 15, 2003·The Journal of Biological Chemistry·David A SolomonErik S Knudsen
Sep 27, 2003·European Journal of Biochemistry·Benoît Palancade, Olivier Bensaude
Oct 11, 2003·Molecular Cell·Manuel de la MataAlberto R Kornblihtt
Feb 24, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bruno FuchsRalf Janknecht
Aug 28, 2004·Endocrinology·Maofu FuRichard G Pestell
Jan 20, 2005·Gene·Stefan StammHermona Soreq
May 20, 2005·Current Opinion in Cell Biology·David L Bentley
Sep 16, 2005·Journal of Cellular Biochemistry·Andrew B Gladden, J Alan Diehl
Dec 13, 2005·Nature Structural & Molecular Biology·Eric BatschéChristian Muchardt
Feb 8, 2006·Proceedings of the National Academy of Sciences of the United States of America·Craig J BurdKaren E Knudsen
Mar 21, 2006·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Julian P Venables
Jun 22, 2006·Journal of Cell Science·Anabella Srebrow, Alberto R Kornblihtt
Aug 4, 2006·Molecular Cell·B Matija Peterlin, David H Price
Aug 22, 2006·Nature Structural & Molecular Biology·Imke ListermanKarla M Neugebauer
Sep 23, 2006·Nature Reviews. Cancer·Yves Pommier
Nov 3, 2006·Genes & Development·Hemali P Phatnani, Arno L Greenleaf
Feb 27, 2007·Trends in Endocrinology and Metabolism : TEM·Didier AuboeufBert W O'Malley
May 8, 2007·Cancer Cell·Franck TirodeOlivier Delattre

❮ Previous
Next ❯

Citations

Aug 6, 2013·Chromosoma·Camilla Iannone, Juan Valcárcel
May 1, 2008·Molecular Biology Reports·Jack WuD Joshua Liao
Oct 26, 2010·Nature Structural & Molecular Biology·Martin DutertreDidier Auboeuf
Jun 15, 2010·Oncogene·E C ToomeyS L Lessnick
May 3, 2011·The Journal of Biological Chemistry·Kelly A FranceChristopher T Denny
Aug 13, 2013·Nucleic Acids Research·Gautier StollOlivier Delattre
Nov 3, 2010·Genes & Development·Charles J David, James L Manley
Dec 18, 2010·Genome Research·Joanna Y IpBenjamin J Blencowe
May 13, 2010·Cancer Research·Nicholas A OlshavskyKaren E Knudsen
Aug 27, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Clay E S ComstockKaren E Knudsen
Jun 16, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Hayriye V ErkizanJeffrey A Toretsky
May 13, 2010·Molecular Cancer·Véronique MarsaudBrigitte Sola
Feb 17, 2010·Genome Medicine·Heinrich Kovar
Oct 26, 2013·International Journal of Cell Biology·Silvia C LenzkenSilvia M L Barabino
Nov 6, 2010·Sarcoma·Ashley A KowalewskiStephen L Lessnick
Sep 19, 2014·Biogerontology·Danae Campos-MeloMichael J Strong
May 11, 2011·The Journal of Biological Chemistry·Hans-Jörg WarnatzMarie-Laure Yaspo
Nov 4, 2015·Biomolecules·Lulzim Shkreta, Benoit Chabot
Mar 5, 2015·Proceedings of the National Academy of Sciences of the United States of America·Saravana P SelvanathanJeffrey A Toretsky
Apr 9, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Zhenzhen ZengXiangmei Chen
Mar 25, 2009·Current Opinion in Cell Biology·Britta Hartmann, Juan Valcárcel
Nov 28, 2012·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Rui Chen, Michael Snyder
Feb 11, 2012·International Journal of Cancer. Journal International Du Cancer·Aleksandar BoroFelix K Niggli
Aug 27, 2013·Carcinogenesis·Chul Jang KimHirokazu Inoue
Oct 2, 2013·International Journal of Cell Biology·Maria Paola Paronetto
Aug 8, 2013·Biochimica Et Biophysica Acta·Chul-Woong PyoSang-Yun Choi
May 13, 2014·Cell Reports·Maria Paola ParonettoJuan Valcárcel
Aug 6, 2011·Molecular Cell·Maria Paola ParonettoJuan Valcárcel
Aug 23, 2012·Biochemical and Biophysical Research Communications·Eun Jung SohnYun-Ping Wu
Jun 2, 2016·Human Pathology·Sang Kyum Kim, Yong-Koo Park
Apr 8, 2014·Biochemical and Biophysical Research Communications·Xiufeng ChuFengmin Lu
Oct 1, 2013·Drug Discovery Today. Therapeutic Strategies·Lee Spraggon, Luca Cartegni
Jan 30, 2013·Current Opinion in Cell Biology·Alisa A MuellerThomas A Rando
Dec 18, 2019·International Journal of Cancer. Journal International Du Cancer·Beiping MiaoSmiths Lueong

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