Mammalian Elongin A Is Not Essential for Cell Viability but Is Required for Proper Cell Cycle Progression with Limited Alteration of Gene Expression

Yamazaki, Kanami; Aso, Teijiro; Ohnishi, Yoshinori N.; Ohno, Mizuki; Takagi, Kenji; Shuin, Taro; Kitajima, Shigetaka; Nakabeppu, Yusaku

doi:10.1074/jbc.c300047200

Cited by 18 publications

(15 citation statements)

References 30 publications

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“…Previous studies suggested that Elongin A is not generally required for transcription in vivo (19,28). Supporting this idea, shRNA-mediated depletion of Elongin A or deletion of the Elongin A gene neither altered the distribution of RNAPII in cell nuclei nor impaired production of the majority of nascent RNA (Fig.…”

Section: Discussionsupporting

confidence: 64%

“…We previously carried out a comprehensive microarray analysis that revealed that expression of only a small fraction of genes (ϳ3-4%) is affected in Elongin A-deficient mouse ES cells, raising the possibility that Elongin A is not a global regulator of gene expression but rather controls the expression of select genes (28). More recently, we have generated Elongin A-deficient mice (29) and showed that Elongin A plays a crucial role in expression of a variety of genes for neural development (19).…”

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confidence: 99%

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Transcriptional Properties of Mammalian Elongin A and Its Role in Stress Response

Kawauchi

Inoue

Fukuda

et al. 2013

Journal of Biological Chemistry

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Background: Transcriptional elongation is a rate-limiting step in activation of stress response genes. Results: Optimal expression of stress response regulator ATF3 requires the elongation activity but not the ubiquitination activity of Elongin A. Conclusion: Elongin A plays a key role for the adequate expression of ATF3 in vivo. Significance: RNAPII ubiquitination and transcriptional elongation are independent activities of Elongin A.

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Section: Discussionsupporting

confidence: 64%

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confidence: 99%

Transcriptional Properties of Mammalian Elongin A and Its Role in Stress Response

Kawauchi

Inoue

Fukuda

et al. 2013

Journal of Biological Chemistry

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“…Previously, we demonstrated that one of the proteins in this class, dELL, is essential in Drosophila and is not functionally redundant with other members (10). A recent report by Yamazaki et al indicates that mammalian elongin A is not essential for viability of mouse ES cells but is important for proper cell cycle progression and expression of a specific subset of genes (43). Whether elongin A is required for normal mouse development is not known.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Requirement of the RNA Polymerase II Elongation Factor Elongin A for Proper Gene Expression and Development

Gerber¹,

Eissenberg²,

Kong

et al. 2004

Molecular and Cellular Biology

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A number of transcription factors that increase the catalytic rate of mRNA synthesis by RNA polymerase II (Pol II) have been purified from higher eukaryotes. Among these are the ELL family, DSIF, and the heterotrimeric elongin complex. Elongin A, the largest subunit of the elongin complex, is the transcriptionally active subunit, while the smaller elongin B and C subunits appear to act as regulatory subunits. While much is known about the in vitro properties of elongin A and other members of this class of elongation factors, the physiological role(s) of these proteins remain largely unclear. To elucidate in vivo functions of elongin A, we have characterized its Drosophila homologue (dEloA). dEloA associates with transcriptionally active puff sites within Drosophila polytene chromosomes and exhibits many of the expected biochemical and cytological properties consistent with a Pol II-associated elongation factor. RNA interference-mediated depletion of dEloA demonstrated that elongin A is an essential factor that is required for proper metamorphosis. Consistent with this observation, dEloA expression peaks during the larval stages of development, suggesting that this factor may be important for proper regulation of developmental events during these stages. The discovery of the role of elongin A in an in vivo model system defines the novel contribution played by RNA polymerase II elongation machinery in regulation of gene expression that is required for proper development.The mechanism of eukaryotic mRNA synthesis is complex. During its trek down DNA templates, RNA polymerase II (Pol II) encounters many obstacles. To overcome these obstacles, Pol II requires a variety of proteins known as transcription elongation factors. Biochemically distinct from the basal transcription machinery, these proteins have the ability to increase the kinetic rate of mRNA chain elongation by the multiprotein Pol II complex (24,[28][29][30][31][32]34,35,38). One class of elongation factors, which functions by increasing the overall K m and/or the V max of elongating polymerase by decreasing the duration and/or frequency of transient pausing as Pol II progresses along DNA templates, includes the ELL family (ELL, ELL2, ELL3, and dELL) and the elongin proteins (2-4, 14, 25, 36, 37, 44).Elongin was originally purified from rat liver nuclear extracts based on its ability to increase the catalytic rate of transcription by Pol II in an in vitro assay (4). Elongin is a heterotrimeric protein complex comprised of a ϳ110-kDa subunit (elongin A), an ϳ18-kDa subunit (elongin B), and a ϳ15-kDa subunit (elongin C) (2, 4, 12, 13). Elongin A is the transcriptionally active component of this complex, since addition of this protein alone to in vitro transcription assays is capable of stimulating elongation activity. The B and C subunits of the complex function as positive regulators and are unable to stimulate elongation in the absence of the A subunit (1, 4). To date, four elongin A family members have been identified, including a single elongin A homol...

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“…17 Exons 8-10 of the Elongin A gene were replaced with a neomycin cassette in the gene-targeting vector (Figure 1a). 18 The mutant ES cell clones with a disrupted Elongin A locus were used to obtain the germline chimeras that, in turn, were used to generate the heterozygous F1 mutant mice. The genotypes were determined using the polymerase chain reaction (PCR), and the loss of Elongin A expression was confirmed by reverse transcriptase (RT)-PCR (Figure 1b and c).…”

Section: Resultsmentioning

confidence: 99%

“…Elongin A mutant ES cell clones were generated as described previously 18 and microinjected into blastocysts for the generation of chimeric mice. Chimeric males were crossed with C57BL/6 females, and agouti-colored offspring were analyzed for the germline transmission of the Elongin A mutation.…”

Section: Methodsmentioning

confidence: 99%

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A

et al. 2006

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Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To gain more insight into the physiological functions of Elongin A, we generated Elongin A-deficient mice. Elongin A homozygous mutant (Elongin A À/À ) embryos demonstrated a severely retarded development and died at between days 10.5 and 12.5 of gestation, most likely due to extensive apoptosis. Moreover, mouse embryonic fibroblasts (MEFs) derived from Elongin A À/À embryos exhibited not only increased apoptosis but also senescence-like growth defects accompanied by the activation of p38 MAPK and p53. Knockdown of Elongin A in MEFs by RNA interference also dramatically induced the senescent phenotype. A study using inhibitors of p38 MAPK and p53 and the generation of Elongin A-deficient mice with p53-null background suggests that both the p38 MAPK and p53 pathways are responsible for the induction of senescence-like phenotypes, whereas additional signaling pathways appear to be involved in the mediation of apoptosis in Elongin A À/À cells. Taken together, our results suggest that Elongin A is required for the transcription of genes essential for early embryonic development and downregulation of its activity is tightly associated with cellular senescence. Cell Death and Differentiation (2007) Eukaryotic mRNA synthesis by RNA polymerase II (pol II) is regulated by the concerted action of a set of transcription factors that control the activity of pol II during the initiation and elongation stages of transcription. At least six general transcription factors have been identified in eukaryotic cells and found to promote the selective binding of pol II to promoters and to support the basal level of transcription. 1 In addition, a diverse collection of elongation factors that promote efficient elongation of transcripts by pol II in vitro have also been identified. 2-4 These factors fall into two broad functional classes based on their ability to either reactivate arrested pol II or suppress the transient pausing of pol II. The first class is composed of members of the SII family. 3,5 The second class comprises a collection of elongation factors, including TFIIF, 6 Elongin, 7,8 ELL 9 and CSB, 10 which increase the overall rate of mRNA chain elongation by decreasing the frequency and/or duration of transient pausing of pol II at sites along the DNA template.Elongin was identified as a heterotrimer composed of A, B and C subunits of B770, 118 and 112 amino acids, respectively. 7,8,11,12 Elongin A is the transcriptionally active subunit, whereas Elongins B and C are positive regulatory subunits that can form an isolable Elongin BC subcomplex. 8,13,14 Although the functions of Elongin A in vivo remain largely unclear, Gerber et al. 15 have recently reported that the Drosophila homolog of Elongin A (dEloA) colocalizes with pol II at sites of active transcription on polytene chromosomes, and it also plays a critical role in heat shock gene expression in vivo. 15,16 Moreover, by the RNA interference (...

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Mammalian Elongin A Is Not Essential for Cell Viability but Is Required for Proper Cell Cycle Progression with Limited Alteration of Gene Expression

Cited by 18 publications

References 30 publications

Transcriptional Properties of Mammalian Elongin A and Its Role in Stress Response

Transcriptional Properties of Mammalian Elongin A and Its Role in Stress Response

In Vivo Requirement of the RNA Polymerase II Elongation Factor Elongin A for Proper Gene Expression and Development

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A

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