Mapping acetylation sites in E2A identifies a conserved lysine residue in activation domain 1 that promotes CBP/p300 recruitment and transcriptional activation

Hyndman, Brandy D.; Thompson, Patrick; Denis, Christopher M.; Chitayat, Seth; Bayly, Richard; Smith, Steven P.; LeBrun, David P.

doi:10.1016/j.bbagrm.2011.11.013

Cited by 10 publications

(9 citation statements)

References 19 publications

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“…However, it remains possible that elements within AD1 or AD2 of E2A can also interact with these other domains of CBP/p300 in conjunction with the KIX domain, which could account for the apparent cooperativity of AD1 and AD2 with respect to CBP/p300 recruitment. Given that E2A is a target of phosphorylation and acetylation (38,65–70), including at the N-terminus and central region where AD1 and AD2 are located, respectively, these post-translational modifications could alter the binding affinities and specificities for the various domains of CBP/p300.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the KIX domain of CBP/p300 interacts directly with ϕ-x-x-ϕ-ϕ sequences within the PCET motif of E2A and in the ADs of p53, mixed lineage leukemia (MLL) and FOXO3a (28,31–35). Direct binding of E2A to the KIX domain of CBP/p300 results in acetylation of E2A and enhanced acetyltransferase activity of CBP/p300 (20,22,32,36–38). …”

Section: Introductionmentioning

confidence: 99%

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Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300

Denis

Langelaan

Kirlin

et al. 2014

Nucleic Acids Research

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The E-protein transcription factors play essential roles in lymphopoiesis, with E12 and E47 (hereafter called E2A) being particularly important in B cell specification and maturation. The E2A gene is also involved in a chromosomal translocation that results in the leukemogenic oncoprotein E2A-PBX1. The two activation domains of E2A, AD1 and AD2, display redundant, independent, and cooperative functions in a cell-dependent manner. AD1 of E2A functions by binding the transcriptional co-activator CBP/p300; this interaction is required in oncogenesis and occurs between the conserved ϕ-x-x-ϕ-ϕ motif in AD1 and the KIX domain of CBP/p300. However, co-activator recruitment by AD2 has not been characterized. Here, we demonstrate that the first of two conserved ϕ-x-x-ϕ-ϕ motifs within AD2 of E2A interacts at the same binding site on KIX as AD1. Mutagenesis uncovered a correspondence between the KIX-binding affinity of AD2 and transcriptional activation. Although AD2 is dispensable for oncogenesis, experimentally increasing the affinity of AD2 for KIX uncovered a latent potential to mediate immortalization of primary hematopoietic progenitors by E2A-PBX1. Our findings suggest that redundancy between the two E2A activation domains with respect to transcriptional activation and oncogenic function is mediated by binding to the same surface of the KIX domain of CBP/p300.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300

Denis

Langelaan

Kirlin

et al. 2014

Nucleic Acids Research

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“…TCF4-FL contains a basic helix-loop-helix DNA binding and dimerization domain along with two activation domains (AD1 and AD2), while TCF4-S lacks AD1. TCF4 shares high amino acid sequence homology in its AD1 with AD1 from TCF3 (also called E2A), particularly in a conserved motif that recruits the transcriptional coactivators CBP and p300 (61,62). We would therefore expect that TCF4-FL, which contains AD1 and is downregulated in LCLs, promotes transcription at the Z promoter through recruitment of CBP and p300.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Induces Global Changes in Cellular mRNA Isoform Usage That Are Important for the Maintenance of Latency

Homa

Salinas

Forte

et al. 2013

J Virol

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Oncogenic viruses promote cell proliferation through the dramatic reorganization of host transcriptomes. In addition to regulating mRNA abundance, changes in mRNA isoform usage can have a profound impact on the protein output of the transcriptome. Using Epstein-Barr virus (EBV) transformation of primary B cells, we have studied the ability of an oncogenic virus to alter the mRNA isoform profile of its host. Using the algorithm called SplicerEX with two complementary Affymetrix microarray platforms, we uncovered 433 mRNA isoform changes regulated by EBV during B-cell transformation. These changes were largely orthogonal with the 2,163 mRNA abundance changes observed during transformation, such that less than one-third of mRNAs changing at the level of isoform also changed in overall abundance. While we observed no preference for a mechanistic class of mRNA isoform change, we detected a significant shortening of 3= untranslated regions and exclusion of cassette exons in EBVtransformed cells relative to uninfected B cells. Gene ontology analysis of the mRNA isoform changes revealed significant enrichment in nucleic acid binding proteins. We validated several of these isoform changes and were intrigued by those in two mRNAs encoding the proteins XBP1 and TCF4, which have both been shown to bind and activate the promoter of the major EBV lytic trans-activator BZLF1. Our studies indicate that EBV latent infection promotes the usage of mRNA isoforms of XBP1 and TCF4 that restrict BZLF1 activation. Therefore, characterization of global changes in mRNA isoform usage during EBV infection identifies a new mechanism for the maintenance of latent infection.

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“…E2A-PBX1a is the most common form in pediatric pre-B ALL. 27 Previous reports have indicated that E2A is acetylated by the HATs p300 and CBP 17,18 via a mechanism dependent on the E2A LXXLL motif. E2A also contains the STAGA (GCN5-containing) HAT complex binding motif LDFS (see Figure 1b), which has been shown to be important for E2A-PBX1-driven oncogenesis in ALL.…”

Section: E2a-pbx1 Is Acetylated By Gcn5mentioning

confidence: 99%

“…More recently it was reported that a conserved lysine at position 34 of the E2A AD1 is acetylated by CBP/p300, and acetylation of Lys34 was shown to promote binding of CBP/ p300, as well as E2A-mediated transcriptional activation. 18 Lys34 is in close proximity to the overlapping conserved LXXLL and LDFS motifs at amino-acid positions 16-23 of the E2A AD1 (see Figure 1b). LXXLL can directly interact with the KIX domain (also called the CREB-binding domain) of CBP/p300.…”

Section: Introductionmentioning

confidence: 96%

GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia

et al. 2012

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The t(1;19) translocation in pediatric pre-B-cell acute lymphoblastic leukemia (ALL) fuses the genes, which encode the transcriptional activator E2A and homeobox pre-B-cell leukemia transcription factor 1 (PBX1), resulting in expression of the chimeric transcription factor E2A-PBX1. E2A-PBX1 can promote cell transformation both in vitro and in vivo; however, the mechanisms by which E2A-PBX1 contributes to malignancy merit further investigation. In the current work we report, for the first time, a physical and functional interaction between the SPT3-TAFII31-GCN5L acetylase (STAGA) complex and E2A-PBX1. STAGA, and its acetyltransferase subunit GCN5, directly interacted with the E2A portion of E2A-PBX1. GCN5 acetylated E2A-PBX1 and increased the stability of E2A-PBX1 protein in cells. Moreover, the GCN5 inhibitor α-methylene-γ-butyrolactone 3 (MB-3) decreased E2A-PBX1 acetylation and E2A-PBX1 protein levels in leukemic cells, indicating that GCN5 inhibitors have potential value as therapeutic agents for ALL. In addition, we show that the E3 ubiquitin ligase HDM2 potentiates the degradation of E2A-PBX1. We suggest that dynamic regulation of E2A-PBX1 protein levels in vivo has a fundamental role in ALL.

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Mapping acetylation sites in E2A identifies a conserved lysine residue in activation domain 1 that promotes CBP/p300 recruitment and transcriptional activation

Cited by 10 publications

References 19 publications

Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300

Functional redundancy between the transcriptional activation domains of E2A is mediated by binding to the KIX domain of CBP/p300

Epstein-Barr Virus Induces Global Changes in Cellular mRNA Isoform Usage That Are Important for the Maintenance of Latency

GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia

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