Regulation of the Ets-1 transcription factor by sumoylation and ubiquitinylation

Ji, Zongling; Degerny, Cindy; Vintonenko, N; Deheuninck, Julien; Foveau, Bénédicte; Leroy, Catherine; Cottet, J; Tulasne, David; Baert, Jean-Luc; Fafeur, Véronique

doi:10.1038/sj.onc.1209789

Cited by 51 publications

(57 citation statements)

References 48 publications

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“…MT does seem to upregulate PEA3 RNA levels (not shown), but it is likely that the promoter regulation seen here is also a result of modifications. The Ets family is regulated by phosphorylation (103), acetylation (19), and sumoylation (48). For example, Ets-1 is positively regulated via phosphorylation by extracellular-signal-related kinase (ERK) at threonine 38 (16,64,93,99).…”

Section: Discussionmentioning

confidence: 99%

Polyomavirus Middle T Antigen Induces the Transcription of Osteopontin, a Gene Important for the Migration of Transformed Cells

Whalen

Weber

Benjamin

et al. 2008

J Virol

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Middle T antigen (MT) is the principal oncoprotein of murine polyomavirus. Experiments on the acute immediate effects of MT expression on cellular RNA levels showed that expression of osteopontin (OPN) was strongly induced by MT expression. Osteopontin is a protein known to be associated with cancer. It has a role in tumor progression and invasion. Protein analysis confirmed that MT induced the secretion of OPN into the extracellular medium. Expression of antisense OPN RNA had no effect on the growth of MT-transformed cells. However, it had a strong effect on the ability of MT transformants to migrate or to fill a wound. Analysis of MT mutants implicated both the SHC and phosphatidylinositol 3-kinase pathways in OPN induction. Reporter assays showed that MT regulated the OPN promoter through two of its PEA3 (polyoma enhancer activator 3) sites. As critical PEA3 sites are also part of the polyomavirus enhancer, the same signaling important for viral replication also contributes to virally induced metastatic potential.Murine polyomavirus causes a broad range of tumors in various types of cells and has been a valuable model for studying growth regulation (21,29,33). Middle T antigen (MT) is the principal oncoprotein of polyomavirus that is necessary (9, 79) and often sufficient (81) for transformation in vitro. MT delivered as a transgene or a retrovirus can induce tumors in a wide variety of tissues (5,38,55,78,104). Viruses carrying mutant MTs often are defective for transformation in vitro or tumorigenesis in vivo (7,18,35,100). Similarly, transgenic mutant MTs show different phenotypes from the wild type (96).MT is associated with membranes and underlying cytoskeletal elements (2,46,69,75). Its ability to transform depends upon that association (9). MT functions as a kind of adaptor, on which cellular signaling proteins are assembled. It binds the A and C subunits of protein phosphatase 2A (63, 90). As a result of this association, MT is able to bind protein tyrosine kinases of the SRC family (SRC, YES, and FYN) (15,17,42,52). In the protein tyrosine kinase complex, MT is phosphorylated on three major tyrosine residues: 315, 322, and 250 (10,39,44,68). Each of these sites represents a connection to a signal generator: 315 to phosphatidylinositol 3-kinase (PI3K) and one or more additional interacting proteins (41, 49, 97), 250 to SHC (8, 24) and thence to GRB2 and SOS, and 322 to phospholipase C-␥1 (PLC-␥1) (77) and potentially PI3K as well. Mutation of amino acid 322 has had a modest effect in some transformation assays (57), but there is a striking effect at low serum concentration (77). Mutation of tyrosine 250 has a dramatic effect on MT transforming ability (57), as do mutations in the regions amino terminal to position 250 (the NPTY motif) (27,28). Tyrosine 250 represents part of the binding site for the adaptor SHC, and that binding leads to tyrosine phosphorylation of SHC (8, 24). In turn, SHC binding and tyrosine phosphorylation are responsible for the recruitment of GRB2. Association with PI3K is profo...

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Section: Discussionmentioning

confidence: 99%

Polyomavirus Middle T Antigen Induces the Transcription of Osteopontin, a Gene Important for the Migration of Transformed Cells

Whalen

Weber

Benjamin

et al. 2008

J Virol

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“…The N terminus of Ets1 also contains a lysine residue (K15) that is subjected to modification by SUMOylation (33)(34)(35). SUMOylation of Ets1 inhibits its transactivation potential (33,35). The recruitment of SUMOylation enzymes to Ets1 does not depend on interactions with the Pointed domain (34).…”

Section: Ets1 But Not Ets2 Inhibits Asc Differentiationmentioning

confidence: 99%

“…An Ets1 mutant lacking the N terminus of Ets1 (amino acids 1 to 54) lacks the Erk phosphorylation site and thus cannot be phosphorylated and will be less effective at activating target genes. The N terminus of Ets1 also contains a lysine residue (K15) that is subjected to modification by SUMOylation (33)(34)(35). SUMOylation of Ets1 inhibits its transactivation potential (33,35).…”

Section: Ets1 But Not Ets2 Inhibits Asc Differentiationmentioning

confidence: 99%

Transcription Factor Ets1, but Not the Closely Related Factor Ets2, Inhibits Antibody-Secreting Cell Differentiation

John

Russell

Chin

et al. 2014

Molecular and Cellular Biology

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bB cell differentiation into antibody-secreting cells (ASCs) is a tightly regulated process under the control of multiple transcription factors. One such transcription factor, Ets1, blocks the transition of B cells to ASCs via two separate activities: (i) stimulating the expression of target genes that promote B cell identity and (ii) interfering with the functional activity of the transcription factor Blimp1. Ets1 is a member of a multigene family, several members of which are expressed within the B cell lineage, including the closely related protein Ets2. In this report, we demonstrate that Ets1, but not Ets2, can block ASC formation despite the fact that Ets1 and Ets2 bind to apparently identical DNA sequence motifs and are thought to regulate overlapping sets of target genes. The DNA binding domain of Ets1 is required, but not sufficient by itself, to block ASC formation. In addition, less conserved regions within the N terminus of Ets1 play an important role in inhibiting B cell differentiation. Differences between the N termini of Ets1 and Ets2, rather than differences in the DNA binding domains, determine whether the proteins are capable of blocking ASC formation or not.

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“…In the shorter term, the identification of multiple target genes that mediate the ETS and/or ETS-AR transcriptional response may identify novel prognostic markers that may Regulates AR transcriptional activity [11] DAXX Death domain protein ETS1 Represses transcriptional activity [59] Negatively regulates AR [60] ER Nuclear receptor ETS1 Ligand independent co-regulation [20] Direct promoter interactions [61] FLNA Cytoskeleton organization PDEF Proteomic analysis associated [62] Regulates AR and co-regulatory proteins [11] GATA1 Transcription factor FLI1 Ligand independent co-regulation [50,63] Regulates AR co-regulatory factors [64] GATA3 Transcription factor ELF1/ETS1/ETS2 Direct promoter interactions [20,63] Regulates AR/co-regulatory proteins [11] NCoR Receptor co-regulator ETS1/TEL/ETS2 ETS transcriptional repression [55] Nuclear receptor co-regulatory protein [65] NKX3.1 Transcriptional cofactor PDEF Regulate androgen associated genes [32,33] Regulate androgen associated genes [66] OCT1 Transcription factor PU-1/ETS1 Direct promoter interactions [67] AR Transcriptional regulation [11] p53 Transcription factor ETS1 p53 dependent apoptosis [20] p53 negatively regulates AR [11,68] PIASy Sumoylation ETS1 Sumylation independent transcription [56] Sumylation independent transcription [69] SENP1 Sumoylation ETS1 Desumoylates Ets-1 [56] Enhances AR transcriptional activity [70] SRC1 Histone modifier PEA3/ETS1/ETS2 Transcriptional activator [55,71] AR transcriptional co-activator [54] SRC3 Histone modifier ETS2 Ets-2 regulation of myc [72] AR transcriptional co-activator [54] SUMO1 Sumoylation ETV6/ETS1 ETS ubiquitination [73,…”

Section: Future Research Directionsmentioning

confidence: 99%

The Role of ETS Transcriptional Regulation in Hormone Sensitive and Refractory Prostate Cancer

Turner¹

2010

TOCJ

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Most advanced prostate tumors are dependent upon hormonal regulation of the transcriptional activity of the androgen receptor (AR). Current ASCO recommendations for initial treatment of advanced disease target the hormonal mediated regulation of AR activation through androgen deprivation therapy. Despite early treatment efficacy, most prostate tumors progress and re-activate AR transcriptional regulation through alternative biological mechanisms that allow them to circumvent the requirement for androgen. It is the temporal and spatial recruitment of specific AR transcriptional complexes to the promoters of cancer associated target genes that promotes the tumorigenic phenotype in prostate cancer. Increasing published data associates the E Twenty Six (ETS) family of transcription factors with prostate cancer progression and with the transcriptional activity of the AR. Evidence suggests that ETS factors act in concert to both positively and negatively regulate the pathways that control progression to metastatic cancer in prostate tissues. Given the critical roles both ETS factors and the AR play in the development of prostate cancer, mechanistic insight into their transcriptional co-regulation during the hormone sensitive and hormone refractory phases of progression will be provided by determining the contribution of ETS, AR and ETS-AR mediated regulatory control. This review examines the current depth of understanding of the role of the ETS family of transcription factors as transcriptional elements that confer the carcinogenic response to aberrant hormonal activity during prostate cancer progression.

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Regulation of the Ets-1 transcription factor by sumoylation and ubiquitinylation

Cited by 51 publications

References 48 publications

Polyomavirus Middle T Antigen Induces the Transcription of Osteopontin, a Gene Important for the Migration of Transformed Cells

Polyomavirus Middle T Antigen Induces the Transcription of Osteopontin, a Gene Important for the Migration of Transformed Cells

Transcription Factor Ets1, but Not the Closely Related Factor Ets2, Inhibits Antibody-Secreting Cell Differentiation

The Role of ETS Transcriptional Regulation in Hormone Sensitive and Refractory Prostate Cancer

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