title: Mammary gland selective excision of c-jun identifies its role in mRNA splicing.
abstract: The c-jun gene regulates cellular proliferation and apoptosis via direct regulation of cellular gene expression. Alternative splicing of pre-mRNA increases the diversity of protein functions, and alternate splicing events occur in tumors. Here, by targeting the excision of the endogenous c-jun gene within the mouse mammary epithelium, we have identified its selective role as an inhibitor of RNA splicing. Microarray-based assessment of gene expression, on laser capture microdissected c-jun(-/-) mammary epithelium, showed that endogenous c-jun regulates the expression of approximately 50 genes governing RNA splicing. In addition, genome-wide splicing arrays showed that endogenous c-jun regulated the alternate exon of approximately 147 genes, and 18% of these were either alternatively spliced in human tumors or involved in apoptosis. Endogenous c-jun also was shown to reduce splicing activity, which required the c-jun dimerization domain. Together, our findings suggest that c-jun directly attenuates RNA splicing efficiency, which may be of broad biologic importance as alternative splicing plays an important role in both cancer development and therapy resistance.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Covarrubias
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rose
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Talat
authors.initials: T
authors.lastname: Nasim
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D016758:Genes, jun; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012326:RNA Splicing