Identification and Biochemical Characterization of a Novel Transcription Elongation Factor, Elongin A3

Yamazaki, Kanami; Guo, Limei; Sugahara, Kazunori; Chun, Zhang; Enzan, Hideaki; Nakabeppu, Yusaku; Kitajima, Shigetaka; Aso, Teijiro

doi:10.1074/jbc.m202859200

Cited by 27 publications

(30 citation statements)

References 33 publications

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“…Elongin A on the other hand can mediate DNA damage-induced ubiquitination and degradation of the largest subunit of RNA polymerase II together with Elongin BC and the Cul5/Rbx2 module (Yasukawa et al 2008). Like Elongin A and VHL, Elongin A3 possesses the Elongin C binding sequence and can form a putative ubiquitylation complex with Elongin BC and Cul5/Rbx2 (Yamazaki et al 2002). Interestingly, Elongin C (TCEB1) has been shown to be overexpressed and to promote invasion of prostate cancer cells (Jalava et al 2009) metastatic SI-NETs, using a variety of techniques, such as LOH, CGH, CGH-array, SNP analysis, and SNP-array (Kytola et al 2001, Löllgen et al 2001, Tonnies et al 2001, Stancu et al 2003, Wang et al 2005, Kim do et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011, Walsh et al 2011.…”

Section: Discussionmentioning

confidence: 99%

“…Not much is known regarding Elongin A3 function, except that it can form a stable complex with Elongin BC and stimulate elongation by RNA polymerase II in vitro, just like Elongin A (Yamazaki et al 2002). Elongins B (TCEB2) and C (TCEB1) play an important role in tumor suppression by von Hippel-Lindau (VHL), where the VHL protein binds to the same Elongin BC binding sequence as Elongin A (TCEB3) and among other targets also binds to the a subunits of hypoxia-inducible factor and promote their ubiquitination and proteosomal degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Not much is known regarding Elongin A3 function, although it can like Elongin A form a stable complex with Elongin BC and stimulate the rate of transcription elongation by RNA polymerase II in vitro. Like Elongin A, Elongin A3 may be involved in ubiquitin-dependent degradation of proteins (Yamazaki et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

Edfeldt

Ahmad

Åkerström

et al. 2013

Endocrine-Related Cancer

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Small intestinal neuroendocrine tumors (SI-NETs), formerly known as midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. A large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one gene copy of TCEB3C. The DNA hypomethylating agent 5-aza-2 0 -deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease in clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

Edfeldt

Ahmad

Åkerström

et al. 2013

Endocrine-Related Cancer

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“…Elongin constitutes a family of factors, as evidenced by the discovery of the elongin A-related proteins, elongin A2 and elongin A3. Elongin A2 and elongin A3 stimulate the rate of transcriptional elongation, although neither is regulated by elongin B and elongin C (Aso et al 2000;Yamazaki et al 2002). Interestingly, the gene product of the von Hippel-Lindau tumor suppressor (pVHL) can form a stable interaction with the elongin BC proteins (Duan et al 1995;Kibel et al 1995;Conaway et al 1998).…”

Section: Elonginsmentioning

confidence: 99%

Elongation by RNA polymerase II: the short and long of it

Sims¹,

Belotserkovskaya²,

Reinberg³

2004

Genes Dev.

617

586

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Appreciable advances into the process of transcript elongation by RNA polymerase II (RNAP II) have identified this stage as a dynamic and highly regulated step of the transcription cycle. Here, we discuss the many factors that regulate the elongation stage of transcription. Our discussion includes the classical elongation factors that modulate the activity of RNAP II, and the more recently identified factors that facilitate elongation on chromatin templates. Additionally, we discuss the factors that associate with RNAP II, but do not modulate its catalytic activity. Elongation is highlighted as a central process that coordinates multiple stages in mRNA biogenesis and maturation.The regulation of gene expression is one of the most intensely studied areas in all of science. Differential gene expression in multicellular organisms forms the foundation of cell-type specificity. Deregulation of the appropriate pattern of gene expression has profound effects on cellular function and underlies many diseases. Although there are many cellular processes that control gene expression, the most direct regulation occurs during transcription. The transcription of protein-coding genes in eukaryotes is performed by RNA polymerase II (RNAP II). Up until recently, the vast majority of studies aimed at elucidating the molecular mechanisms of transcription regulation have focused on early stages, such as the formation of a transcription initiation complex (preinitiation) and initiation (see below). For many years, transcript elongation has been thought of as the trivial addition of ribonucleoside triphosphates to the growing mRNA chain. It is now apparent that this process is a dynamic and highly regulated stage of the transcription cycle capable of coordinating downstream events. Numerous factors have been identified that specifically target the elongation stage of transcription. Importantly, multiple steps in mRNA maturation, including premRNA capping, splicing, 3Ј-end processing, surveillance, and export, are modulated through interactions with the RNAP II transcript elongation complex (TEC). It also appears that distinct elongation factors function in specific transcriptional contexts; the requirements for these specialized factors are largely unknown and highlight the need to better understand elongation in vivo. Many molecular and biochemical approaches have been used to quantify the different aspects of elongation, many of which are discussed below. It remains important to assimilate both in vitro and in vivo experimental systems when discussing what constitutes an elongation factor. An elongation factor can be defined as any molecule that affects the activities of or is associated with the TEC. We suggest that there are at least two major types of transcript elongation factors: one family, referred to as active elongation factors, and a second family, denoted as passive elongation factors. The difference resides in whether the factor affects the catalytic activity of RNAP II, regardless of whether the factor remains associate...

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“…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 homologue in Caenorhabditis elegans and the closely related elongins A2 and A3 in mammals (3,4,44). Each of these is able to interact with the elongin BC complex via a small sequence motif known as the BC box.…”

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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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Identification and Biochemical Characterization of a Novel Transcription Elongation Factor, Elongin A3

Cited by 27 publications

References 33 publications

TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

Elongation by RNA polymerase II: the short and long of it

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

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