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(Circulation Research. 2008;102:398.)
© 2008 American Heart Association, Inc.

Editorials

Vascular Endothelial Growth Factor Gene Regulation by HEXIM1 in Heart

Atsushi Asakura

From the Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis.

Correspondence to Atsushi Asakura, Stem Cell Institute, University of Minnesota Medical School, McGuire Translational Research Facility, 2001 6th St. SE, Mail Code 2873, Minneapolis, MN 55455. E-mail asakura@umn.edu

See related article, pages 415–422

Key Words: angiogenesis • VEGF • heart • HEXIM1 • C/EBP

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Hexamethylene bis-acetamide (HMBA)-inducible protein 1 (HEXIM1) was cloned as an upregulated gene in vascular smooth muscle cells after treatment with the differentiating agent HMBA.¹ A recent report has shown that HEXIM1 is an inhibitor of positive transcription elongation factor (P-TEF)b, which plays an important role in regulation of RNA polymerase II elongation.^2–4 HEXIM1 was previously cloned as a potential cardiac transcriptional regulatory factor suppressing the cardiac myosin light chain-2v promoter and termed cardiac lineage protein (CLP)-1.⁵ HEXIM1 was also cloned as the novel inhibitor of breast cell growth estrogen-downregulated gene (EDG)1.⁶ HEXIM1 protein level is downregulated by estrogens. HEXIM1 also suppresses estrogen receptor- transcriptional activity.^6,7 Gene and protein expression indicate the broad expression of HEXIM1 during postnatal development, with highest levels in heart, skeletal muscle, and brain. Protein localization of endogenous HEXIM1 in vascular smooth muscle cells and primary cardiomyocytes suggests that HEXIM1 is a nuclear protein. Furthermore, HEXIM1 has been shown to be involved in many biological processes, including cancers, AIDS, cardiac hypertrophy, and inflammation, through transcriptional repression.⁴

In vitro experiments demonstrate that HEXIM1 functions as a transcriptional repressor by inhibiting P-TEFb, a protein complex composed of cyclin-dependent kinase 9 and a cyclin partner that regulates RNA polymerase II elongation.^2–4 HEXIM1 interacts with 7SK small nuclear RNA (snRNA), a component of P-TEFb complex containing cyclin-dependent kinase 9 and cyclin T1. This interaction occurs through the KHRR 7SK snRNA binding motif of HEXIM1 (Figure). HEXIM1 also associates with cyclin T1 through the PYNT motif to suppress P-TEFb activity . . . [Full Text of this Article]