SON Controls Cell-Cycle Progression by Coordinated Regulation of RNA Splicing

Ahn, Eun Young; DeKelver, Russell C.; Lo, Miao Chia; Nguyen, Thao Thi Thu; Matsuura, Shinobu; Boyapati, Anita; Pandit, Shatakshi; Fu, Xiang Dong; Zhang, Dong Er

doi:10.1016/j.molcel.2011.03.014

Cited by 146 publications

(273 citation statements)

References 34 publications

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“…Ubiquitination plays a crucial role in the nuclear factor‐κB (NFκB) pathway, endocytic trafficking, DNA repair, and protein degradation (Grabbe et al, 2011). SON acts as an mRNA splicing cofactor and promotes splicing of many cell‐cycle and DNA‐repair transcripts (Ahn et al, 2011). Since these proteins were the only ones identified that showed an opposing expression pattern comparing the identified proteins positively or negatively correlating to the specific productivity in the transgene delivery comparison of 2F5‐ and 3D6‐scFv‐Fc producers, we believe that these proteins might play a crucial role in cellular regulations leading to the observed phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Proteomic differences in recombinant CHO cells producing two similar antibody fragments

Sommeregger

Mayrhofer

Steinfellner

et al. 2016

Biotech & Bioengineering

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Chinese hamster ovary (CHO) cells are the most commonly used mammalian hosts for the production of biopharmaceuticals. To overcome unfavorable features of CHO cells, a lot of effort is put into cell engineering to improve phenotype. “Omics” studies investigating elevated growth rate and specific productivities as well as extracellular stimulus have already revealed many interesting engineering targets. However, it remains largely unknown how physicochemical properties of the recombinant product itself influence the host cell. In this study, we used quantitative label‐free LC‐MS proteomic analyses to investigate product‐specific proteome differences in CHO cells producing two similar antibody fragments. We established recombinant CHO cells producing the two antibodies, 3D6 and 2F5, both as single‐chain Fv‐Fc homodimeric antibody fragments (scFv‐Fc). We applied three different vector strategies for transgene delivery (i.e., plasmid, bacterial artificial chromosome, recombinase‐mediated cassette exchange), selected two best performing clones from transgene variants and transgene delivery methods and investigated three consecutively passaged cell samples by label‐free proteomic analysis. LC‐MS‐MS profiles were compared in several sample combinations to gain insights into different aspects of proteomic changes caused by overexpression of two different heterologous proteins. This study suggests that not only the levels of specific product secretion but the product itself has a large impact on the proteome of the cell. Biotechnol. Bioeng. 2016;113: 1902–1912. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Proteomic differences in recombinant CHO cells producing two similar antibody fragments

Sommeregger

Mayrhofer

Steinfellner

et al. 2016

Biotech & Bioengineering

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“…The mechanisms by which these splicing factors affect mitosis, however, are not known. Recently, the ubiquitin specific peptidase 4 (USP4) was found to be required for the splicing of Bub1 (48), whereas depletion of the serine/arginine-rich splicing factor SON causes pleotropic mitotic defects (49). ERH is likely to operate in a distinct pathway, because it is required for the splicing of CENP-E pre-mRNA for the expression of Bub1, BubR1, MAD2, or PLK1.…”

Section: Discussionmentioning

confidence: 99%

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

Weng

Lee

Shu

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.synthetic lethality | spliceosome

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“…Immunoprecipitation: precleared lysate incubated 4 h-overnight at 4°C with antibody and washed 5 times with lysis buffer. 16 Antibodies: N-CoR (Abcam); Flag, a-tubulin (Sigma-Aldrich); CDK4, Cyclin A, Cyclin D3 (Santa Cruz); p27 (BD Biosciences); HA (Covance). The publication costs of this article were defrayed in part by page charge payment.…”

Section: Methodsmentioning

confidence: 99%

“…[13][14][15] SON is a DNA-and RNA-binding protein, is involved in regulation of gene transcription and RNA splicing, and is required for cell cycle progression. 16,17 Blocking protein interactions with AML1-ETO Cterminus by overexpression of a SON fragment is sufficient to rescue cells from AML1-ETO-induced growth arrest. 10 C-terminal C663S mutation of AML1-ETO reportedly destroyed the zinc-chelating structure of the NHR4 domain and disrupted N-CoR interaction with NHR4.…”

mentioning

confidence: 99%

Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential

DeKelver¹,

Yan

Ahn

et al. 2013

Blood

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Key Points• AML1-ETO-W692A loses interaction between NHR4 and N-CoR, decreases AML1-ETO cellular dysregulation, and promotes leukemia development in mice.AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development.In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO Cterminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/ transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO. (Blood. 2013;121(18):3714-3717)

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SON Controls Cell-Cycle Progression by Coordinated Regulation of RNA Splicing

Cited by 146 publications

References 34 publications

Proteomic differences in recombinant CHO cells producing two similar antibody fragments

Proteomic differences in recombinant CHO cells producing two similar antibody fragments

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential

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