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The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.

ABSTRACT: Alternative splicing of pre-messenger RNA (mRNA) is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA-binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The carboxy-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk (extracellular signal-regulated protein kinase) pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq, we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk-regulated cell proliferation.

SUBMITTER: Choudhury R

PROVIDER: S-EPMC4146490 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.

Choudhury Rajarshi R Roy Sreerupa Ghose SG Tsai Yihsuan S YS Tripathy Ashutosh A Graves Lee M LM Wang Zefeng Z

Nature communications 20140101

Alternative splicing of pre-messenger RNA (mRNA) is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA-binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The carboxy-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This ...[more]

PMID: 24452013

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Project description:Retinoblastoma (RB) is a common neoplasm that is exhibited in individuals globally. Increasing evidence demonstrated that cyclin‑dependent kinase regulatory subunit 1B (CKS1B) may be involved in the pathogenesis of various tumor types, including multiple myeloma and breast cancer. In the present study, the hypothesis that CKS1B downregulation would effectively inhibit the proliferation, invasion and angiogenesis of RB cells through the mitogen‑activated protein kinase kinase (MEK)/extracellular signal‑regulated kinase (ERK) signaling pathway was examined. Initial investigation of the expression profile of CKS1B in RB and adjacent retina tissues was performed using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. A total of three RB cell lines, SO‑RB50, Y79 and HXO‑RB44, were examined for selection of the cell line with the highest expression of CKS1B, and human normal retinal vascular endothelial cells (ACBRI‑181) were also evaluated. CKS1B short hairpin RNA (shRNA) sequences (shRNA CKS1B‑1, shRNA CKS1B‑2 and shRNA CKS1B‑3) and negative control shRNA sequences were constructed and transfected into cells at the third generation to evaluate the role of shCKS1B and the MEK/ERK signaling pathway in RB. Furthermore, the effect of shCKS1B on cell proliferation, migration, invasion, apoptosis and angiogenesis was investigated. CKS1B was determined to be highly expressed in RB tissue, compared with adjacent retina tissue. SO‑RB50 and HXO‑RB44 cells treated with shRNA CKS1B‑1 and shRNA CKS1B‑2 were selected for the present experiments. Activation of the MEK/ERK signaling pathway increases the expression of MEK, ERK, B‑cell lymphoma 2, proliferating cell nuclear antigen, cyclin D1, vascular endothelia growth factor and basic fibroblast growth factor, enhances cell proliferation, migration, invasion and lumen formation, and decreases apoptosis. Following silencing CKS1B, the aforementioned conditions were reversed. The key observations of the present study demonstrated that shCKS1B can inhibit the proliferation, invasion and angiogenesis of RB cells by suppressing the MEK/ERK signaling pathway. Thus, CKS1B represents a potential research target in the development of therapeutics for RB.

Dataset Information

The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.

Publications

The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.

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