Mammary Gland Selective Excision of c-Jun Identifies Its Role in mRNA Splicing

TY - JOUR

T1 - Mammary Gland Selective Excision of c-Jun Identifies Its Role in mRNA Splicing

AU - Katiyar, Sanjay

AU - Jiao, Xuanmao

AU - Addya, Sankar

AU - Ertel, Adam

AU - Covarrubias, Yolanda

AU - Rose, Vanessa

AU - Casimiro, Mathew C.

AU - Zhou, Jie

AU - Lisanti, Michael P.

AU - Nasim, Talat

AU - Fortina, Paolo

AU - Pestell, Richard G.

PY - 2012/2/15

Y1 - 2012/2/15

N2 - 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. Cancer Res; 72(4); 1023-34. (C) 2011 AACR.

AB - 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. Cancer Res; 72(4); 1023-34. (C) 2011 AACR.

U2 - 10.1158/0008-5472.CAN-11-3647

DO - 10.1158/0008-5472.CAN-11-3647

M3 - Article

VL - 72

SP - 1023

EP - 1034

JO - Cancer Research

JF - Cancer Research

IS - 4

ER -