A Role for the Serine/arginine-rich (SR) Protein B52/SRSF6 in Cell Growth and Myc Expression in Drosophila

Overview

Journal Genetics

Publisher Oxford University Press

Specialty Genetics

Date 2015 Feb 15

PMID 25680814

Citations 7

Authors

Celine Fernando

Agnes Audibert

Francoise Simon

Jamal Tazi

Francois Juge

Affiliations

Soon will be listed here.

Abstract

Serine-/arginine-rich (SR) proteins are RNA-binding proteins that are primarily involved in alternative splicing. Expression of some SR proteins is frequently upregulated in tumors, and previous reports have demonstrated that these proteins can directly participate in cell transformation. Identifying factors that can rescue the effects of SR overexpression in vivo is, therefore, of potential therapeutic interest. Here, we analyzed phenotypes induced by overexpression of the SR protein B52 during Drosophila development and identified several proteins that can rescue these phenotypes. Using the mechanosensory bristle lineage as a developmental model, we show that B52 expression level influences cell growth, but not differentiation, in this lineage. In particular, B52 overexpression increases cell growth, upregulates myc transcription, and gives rise to flies lacking thoracic bristles. Using a genetic screen, we identified several suppressors of the phenotypes induced by overexpression of B52 in vivo in two different organs. We show that upregulation of brain tumor (brat), a tumor suppressor and post-transcriptional repressor of myc, and downregulation of lilliputian (lilli), a subunit of the superelongation complex involved in transcription elongation, efficiently rescue the phenotypes induced by B52 overexpression. Our results demonstrate a role of this SR protein in cell growth and identify candidate proteins that may overcome the effects of SR protein overexpression in mammals.

Citing Articles

Allele-specific alternative splicing of Drosophila Ribosomal protein S21 suppresses a lethal mutation in the Phosphorylated adaptor for RNA export (Phax) gene.

Garcia E G3 (Bethesda). 2022; 12(9).

PMID: 35920767 PMC: 9434302. DOI: 10.1093/g3journal/jkac195.

Targeting Splicing Factor SRSF6 for Cancer Therapy.

She W, Shao J, Jia R Front Cell Dev Biol. 2021; 9:780023.

PMID: 34917618 PMC: 8669609. DOI: 10.3389/fcell.2021.780023.

Splicing factor SRSF6 mediates pleural fibrosis.

Liang L, Xiong L, Cheng P, Chen S, Feng X, Zhou Y JCI Insight. 2021; 6(10).

PMID: 33905374 PMC: 8262297. DOI: 10.1172/jci.insight.146197.

Modulation of Yorkie activity by alternative splicing is required for developmental stability.

Srivastava D, de Toledo M, Manchon L, Tazi J, Juge F EMBO J. 2020; 40(3):e104895.

PMID: 33320356 PMC: 7849169. DOI: 10.15252/embj.2020104895.

SRSF6 regulates alternative splicing of genes involved in DNA damage response and DNA repair in HeLa cells.

Yang X, Zhan P, Feng S, Ji H, Tian W, Wang M Oncol Rep. 2020; 44(5):1851-1862.

PMID: 32901876 PMC: 7551351. DOI: 10.3892/or.2020.7750.

References

Ring H, Lis J . The SR protein B52/SRp55 is essential for Drosophila development. Mol Cell Biol. 1994; 14(11):7499-506. PMC: 359286. DOI: 10.1128/mcb.14.11.7499-7506.1994. View

Wittwer F, van der Straten A, Keleman K, Dickson B, Hafen E . Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. Development. 2001; 128(5):791-800. DOI: 10.1242/dev.128.5.791. View

Michelotti E, Michelotti G, Aronsohn A, Levens D . Heterogeneous nuclear ribonucleoprotein K is a transcription factor. Mol Cell Biol. 1996; 16(5):2350-60. PMC: 231223. DOI: 10.1128/MCB.16.5.2350. View

Gho M, Lecourtois M, Geraud G, Posakony J, Schweisguth F . Subcellular localization of Suppressor of Hairless in Drosophila sense organ cells during Notch signalling. Development. 1996; 122(6):1673-82. DOI: 10.1242/dev.122.6.1673. View

Pignoni F, Zipursky S . Induction of Drosophila eye development by decapentaplegic. Development. 1997; 124(2):271-8. DOI: 10.1242/dev.124.2.271. View

Shi H, Hoffman B, Lis J . RNA aptamers as effective protein antagonists in a multicellular organism. Proc Natl Acad Sci U S A. 1999; 96(18):10033-8. PMC: 17837. DOI: 10.1073/pnas.96.18.10033. View

Jumaa H, Wei G, Nielsen P . Blastocyst formation is blocked in mouse embryos lacking the splicing factor SRp20. Curr Biol. 1999; 9(16):899-902. DOI: 10.1016/s0960-9822(99)80394-7. View

Johnston L, Prober D, Edgar B, Eisenman R, Gallant P . Drosophila myc regulates cellular growth during development. Cell. 1999; 98(6):779-90. PMC: 10176494. DOI: 10.1016/s0092-8674(00)81512-3. View

Ji X, Zhou Y, Pandit S, Huang J, Li H, Lin C . SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell. 2013; 153(4):855-68. PMC: 4103662. DOI: 10.1016/j.cell.2013.04.028. View

10.

Zhou Z, Fu X . Regulation of splicing by SR proteins and SR protein-specific kinases. Chromosoma. 2013; 122(3):191-207. PMC: 3660409. DOI: 10.1007/s00412-013-0407-z. View

11.

Xu X, Yang D, Ding J, Wang W, Chu P, Dalton N . ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell. 2005; 120(1):59-72. DOI: 10.1016/j.cell.2004.11.036. View

12.

Oskarsson T, Trumpp A . The Myc trilogy: lord of RNA polymerases. Nat Cell Biol. 2005; 7(3):215-7. DOI: 10.1038/ncb0305-215. View

13.

Xu X, Fu X . Conditional knockout mice to study alternative splicing in vivo. Methods. 2005; 37(4):387-92. DOI: 10.1016/j.ymeth.2005.07.019. View

14.

Betschinger J, Mechtler K, Knoblich J . Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell. 2006; 124(6):1241-53. DOI: 10.1016/j.cell.2006.01.038. View

15.

Fic W, Juge F, Soret J, Tazi J . Eye development under the control of SRp55/B52-mediated alternative splicing of eyeless. PLoS One. 2007; 2(2):e253. PMC: 1803029. DOI: 10.1371/journal.pone.0000253. View

16.

Karni R, de Stanchina E, Lowe S, Sinha R, Mu D, Krainer A . The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007; 14(3):185-93. PMC: 4595851. DOI: 10.1038/nsmb1209. View

17.

Gabut M, Dejardin J, Tazi J, Soret J . The SR family proteins B52 and dASF/SF2 modulate development of the Drosophila visual system by regulating specific RNA targets. Mol Cell Biol. 2007; 27(8):3087-97. PMC: 1899935. DOI: 10.1128/MCB.01876-06. View

18.

Muse G, Gilchrist D, Nechaev S, Shah R, Parker J, Grissom S . RNA polymerase is poised for activation across the genome. Nat Genet. 2007; 39(12):1507-11. PMC: 2365887. DOI: 10.1038/ng.2007.21. View

19.

Wang H, Xu X, Ding J, Bermingham Jr J, Fu X . SC35 plays a role in T cell development and alternative splicing of CD45. Mol Cell. 2001; 7(2):331-42. DOI: 10.1016/s1097-2765(01)00181-2. View

20.

Sonoda J, Wharton R . Drosophila Brain Tumor is a translational repressor. Genes Dev. 2001; 15(6):762-73. PMC: 312658. DOI: 10.1101/gad.870801. View