Identification and Characterization of Elongin A2, a New Member of the Elongin Family of Transcription Elongation Factors, Specifically Expressed in the Testis

Aso, Teijiro; Yamazaki, Kanami; Amimoto, Keiko; Kuroiwa, Asato; Higashi, Hideaki; Matsuda, Yoichi; Kitajima, Shigetaka; Hatakeyama, Masanori

doi:10.1074/jbc.275.9.6546

Cited by 30 publications

(29 citation statements)

References 28 publications

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“…A number of elongation factors appear to have evolved specialized functions in metazoans and are limiting for the expression of specific genes, with mutations that result in very specific phenotypes (10,16,21). Consistent with these observations, Northern blots for elongin A, elongin A2, and elongin A3 reveal differential expression at the tissue level (3,44).…”

Section: Discussionsupporting

confidence: 69%

“…Biochemical data suggest that the elongin family of transcription factors can regulate transcription elongation by Pol II (2)(3)(4)44). Here, we provide the first evidence that an elongin A family protein associates with hyperphosphorylated Pol II on chromosomes in vivo.…”

Section: Discussionmentioning

confidence: 63%

“…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%

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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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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 99%

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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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“…This is in contrast to ELL, which is ubiquitously expressed, and ELL2 which is expressed in most tissues tested except for the kidneys (19). There are other testis-specific RNA polymerase II elongation factors such as SII and elongin A2 (7,30,31). What is the function of these testis elongation factors in vivo?…”

Section: Figmentioning

confidence: 96%

Identification, Cloning, Expression, and Biochemical Characterization of the Testis-specific RNA Polymerase II Elongation Factor ELL3

Miller

Williams

Johnstone

et al. 2000

Journal of Biological Chemistry

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The human ELL gene, which is a frequent target for translocation in acute myeloid leukemia, was initially isolated from rat liver nuclei and found to be an RNA polymerase II elongation factor. Based on homology to ELL, we later cloned ELL2 and demonstrated that it can also increase the catalytic rate of transcription elongation by RNA polymerase II. To better understand the role of ELL proteins in the regulation of transcription by RNA polymerase II, we have initiated a search for proteins related to ELLs. In this report, we describe the molecular cloning, expression, and characterization of ELL3, a novel RNA polymerase II elongation factor approximately 50% similar to both ELL and ELL2. Our transcriptional studies have demonstrated that ELL3 can also increase the catalytic rate of transcription elongation by RNA polymerase II. The C-terminal domain of ELL, which we recently demonstrated to be required and sufficient for the immortalization of myeloid progenitor cells, shares strong similarities to the C-terminal domain of ELL3. ELL3 was localized by immunofluorescence to the nucleus of cells, and Northern analysis indicated that ELL3 is a testis-specific RNA polymerase II elongation factor.Many cellular factors involved in human oncogenesis have been identified as genes at breakpoints of frequently occurring chromosomal translocations. The protein products of some of these genes are transcriptional factors that regulate the general or specific expression of many genes. The ELL gene was initially identified on chromosome 19p13.1, which undergoes frequent translocation with the trithorax-like MLL (ALL-1, HRX) gene on chromosome 11q23 in acute myeloid leukemia (1, 2). ELL is a 621 amino acid-containing protein that can increase the catalytic rate of transcription elongation of RNA polymerase II by suppressing transient pausing at multiple sites along the DNA from both promoter-dependent and promoter-independent templates (3-5). To date, eight elongation factors have been defined biochemically (17,24). These factors are named SII (6 -9), P-TEFb (10 -11), DSIF (11-13), factor 2 (11, 14), TFIIF (15), elongin (SIII) (16), ELL (3, 18), and ELL2 (19). These RNA polymerase II elongation factors fall into several functional classes. Some can prevent arrest, like PTEFb and SII. Some can regulate the rate of transcription elongation through nucleosomes, such as FACT (20). Others operate to increase the catalytic rate of transcription elongation by altering the K m and/or the V max of the polymerase, such as TFIIF, elongin (SIII), the ELL complex, and ELL2 (4, 5).In an effort to better understand how transcription elongation by RNA polymerase II is controlled under normal conditions and in disease states, we are attempting to reconstitute RNA polymerase II transcription elongation machinery in vitro. In so doing, we have now identified and cloned a novel ELL family member, ELL3, and characterized its biochemical role in regulating transcription elongation. MATERIALS AND METHODS Cloning and Expression of ELL3-Searches of GenB...

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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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Identification and Characterization of Elongin A2, a New Member of the Elongin Family of Transcription Elongation Factors, Specifically Expressed in the Testis

Cited by 30 publications

References 28 publications

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

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

Identification, Cloning, Expression, and Biochemical Characterization of the Testis-specific RNA Polymerase II Elongation Factor ELL3

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

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