An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

被引：77

作者：

Adler, Adam S. ^{[1
]}

McCleland, Mark L. ^{[1
]}

Yee, Sharon ^{[2
]}

Yaylaoglu, Murat ^{[1
]}

Hussain, Sofia ^{[1
]}

Cosino, Ely ^{[2
]}

Quinones, Gabriel ^{[3
]}

Modrusan, Zora ^{[4
]}

Seshagiri, Somasekar ^{[4
]}

Torres, Eric ^{[5
]}

Chopra, Vivek S. ^{[1
]}

Haley, Benjamin ^{[4
]}

Zhang, Zemin ^{[6
]}

Blackwood, Elizabeth M. ^{[2
]}

Singh, Mallika ^{[4
]}

Junttila, Melissa ^{[4
]}

Stephan, Jean-Philippe ^{[3
]}

Liu, Jinfeng ^{[6
]}

Pau, Gregoire ^{[6
]}

Fearon, Eric R. ^{[7
]}

Jiang, Zhaoshi ^{[6
]}

Firestein, Ron ^{[1
]}

机构：

[1] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Bioinformat, San Francisco, CA 94080 USA

[7] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

来源：

GENES & DEVELOPMENT | 2014年 / 28卷 / 10期

关键词：

RNAi; PRPF6; tri-snRNP; spliceosome; colon cancer; PRE-MESSENGER-RNA; COLORECTAL-CANCER; SPLICING MACHINERY; NUCLEAR RETENTION; SPLICEOSTATIN-A; TRI-SNRNP; GENE; MUTATIONS; PROTEIN; KINASE;

D O I：

10.1101/gad.237206.113

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the tri-snRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. High-resolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.

引用

页码：1068 / 1084

页数：17

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