Exon 4-encoded acidic domain in the epithelium-restricted Ets factor, ESX, confers potent transactivating capacity and binds to TATA-binding protein (TBP)
被引:25
作者:
Chang, CH
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机构:Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA
Chang, CH
Scott, GK
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机构:Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA
Scott, GK
Baldwin, MA
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机构:Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA
Baldwin, MA
Benz, CC
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机构:Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA
Benz, CC
机构:
[1] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
ESX;
human Ets factor;
genomic organization;
transactivation domain;
D O I:
10.1038/sj.onc.1202674
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
The Ets gene family has a complex evolutionary history with many family members known to regulate genetic programs essential for differentiation and development, and some known for their involvement in human tumorigenesis. To understand the biological properties associated with a recently described epithelium-restricted Ets factor ESX, an 11 kb fragment from the 1q32.2 genomically localized human gene was cloned and analysed. Upstream of the ESX promoter region in this genomic fragment lies the terminal exon of a newly identified gene that encodes a ubiquitin-conjugating enzyme variant, UEV-1. Tissues expressing ESX produce a primary 2.2 kb transcript along with a 4.1 kb secondary transcript arising by alternate poly(A) site selection and uniquely recognized by a genomic probe from the 3' terminal region of the 11 kb clone. Endogenous expression of ESX results in a 42 kDa nuclear protein having fivefold greater affinity for the chromatin-nuclear matrix compartment as compared to other endogenous transcription factors like AP-2 and the homologous Ets factor, ELF-1. Exon mapping of the modular structure inferred from ESX cDNA and construction of GAL4(DBD)-ESX expression constructs were used to identify a transactivating domain encoded by exon 4 having comparable potency to the acidic transactivation domain of the viral transcription factor, VP16. This exon 4-encoded 31 amino acid domain in ESX was shown by mutation and deletion analysis to possess a 13 residue acidic transactivation core which, based on modeling and circular dichroism analysis, is predicted to form an amphipathic alpha-helical secondary structure. Using recombinant GST-ESX (exon 4) fusion proteins in an in vitro pull-down assay, this ESX transactivation domain was shown to bind specifically to one component of the general transcription machinery, TATA-binding protein (TBP). Transient transfection experiments confirmed the ability of this TBP-binding transactivation domain in ESX to squelch heterologous promoters independent of any promoter binding as efficiently as the transactivation domain from VP16.
机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Chen, HM
Gonzalez, DA
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Gonzalez, DA
Radomska, HS
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Radomska, HS
Voso, MT
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Voso, MT
Sun, Z
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Sun, Z
Zhang, P
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Zhang, P
Zhang, DE
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Zhang, DE
Tenen, DG
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机构:
Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Chen, HM
Gonzalez, DA
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Gonzalez, DA
Radomska, HS
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Radomska, HS
Voso, MT
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Voso, MT
Sun, Z
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Sun, Z
Zhang, P
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Zhang, P
Zhang, DE
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机构:Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
Zhang, DE
Tenen, DG
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机构:
Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA