Abstract
Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which controls transcription elongation of RNA polymerase II and Tat transactivation of human immunodeficiency virus. Besides P-TEFb, several proteins have been identified as HEXIM1 binding proteins. It is noteworthy that more than half of the HEXIM1 binding partners are involved in cancers. P53 and two key regulators of the p53 pathway, nucleophosmin (NPM) and human double minute-2 protein (HDM2), are among the factors identified. This review will focus on the functional importance of the interactions between HEXIM1 and p53/NPM/HDM2. NPM and the cytoplasmic mutant of NPM, NPMc+, were found to regulate P-TEFb activity and RNA polymerase II transcription through the interaction with HEXIM1. Importantly, more than one-third of acute myeloid leukemia (AML) patients carry NPMc+, suggesting the involvement of HEXIM1 in tumorigenesis of AML. HDM2 was found to ubiquitinate HEXIM1. The HDM2-mediated ubiquitination of HEXIM1 did not lead to protein degradation of HEXIM1 but enhanced its inhibitory activity on P-TEFb. Recently, HEXIM1 was identified as a novel positive regulator of p53. HEXIM1 prevented p53 ubiquitination by competing with HDM2 in binding to p53. Taken together, the new evidence suggests a role of HEXIM1 in regulating the p53 pathway and tumorigenesis.
Highlights
Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) was initially identified in 1999 by Kusuhara, et al from vascular smooth muscle cells treated with hexamethylene bisacetamide (HMBA), an inhibitor of proliferation [1]
Our results suggest the potential involvement of HEXIM1/positive transcription elongation factor b (P-TEFb) in the tumorigenesis of acute myeloid leukemia (AML) bearing the NPMc+ mutation
P53 is involved in all adult cancers with about 50% of the cancer patients acquiring p53 mutations while the other half is due to the suppression of p53 functions [104]
Summary
Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) was initially identified in 1999 by Kusuhara, et al from vascular smooth muscle cells treated with hexamethylene bisacetamide (HMBA), an inhibitor of proliferation [1]. In 2003, research groups led by Olivier Bensaude and Qiang Zhou revealed a major biological function of HEXIM1 They demonstrated that HEXIM1 associated with positive transcription elongation factor b (P-TEFb) and inhibited its activity [6,7]. NF- B was shown to recruit P-TEFb through the interaction with the p65 subunit, resulting in activation of NF- B-dependent transcription [40]. The N-terminal TA domain, containing amino acids (a.a.) 1–42, recruits the basal transcriptional machinery, such as the TATA box binding protein (TBP) and TBP-associated factors, to activate the expression of p53 target genes [44,45]. NPM is found to interact with HDM2 directly and protect p53 from the HDM2-mediated degradation in an ARF-independent fashion [61] Both HDM2 and NPM are involved in regulation of P-TEFb activity through modulating HEXIM1. Our results suggest the potential involvement of HEXIM1/P-TEFb in the tumorigenesis of AML bearing the NPMc+ mutation
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