Brd4 and HEXIM1: Multiple Roles in P-TEFb Regulation and Cancer

Abstract

Bromodomain-containing protein 4 (Brd4) and hexamethylene bisacetamide (HMBA) inducible protein 1 (HEXIM1) are two opposing regulators of the positive transcription elongation factor b (P-TEFb), which is the master modulator of RNA polymerase II during transcriptional elongation. While Brd4 recruits P-TEFb to promoter-proximal chromatins to activate transcription, HEXIM1 sequesters P-TEFb into an inactive complex containing the 7SK small nuclear RNA. Besides regulating P-TEFb's transcriptional activity, recent evidence demonstrates that both Brd4 and HEXIM1 also play novel roles in cell cycle progression and tumorigenesis. Here we will discuss the current knowledge on Brd4 and HEXIM1 and their implication as novel therapeutic options against cancer.

The Promises of the Novel Connection Between HEXIM and Hedgehog Signalling

“…It is involved in various regulatory processes (transcriptional regulation, p53 pathway), as well as a number of human pathologies (cardiopathies, cancers, inflammation) [1]. Not surprisingly, it has been the focus of numerous mechanistic studies and a potential target of anti-cancer strategies [2,3].…”

“…HEXIM stabilizes p53 through direct protein-protein interaction and prevents HDM2 (human double minute-2 protein)-mediated ubiquitin ligation and its subsequent degradation at the proteasome [1]. The resulting increase of p53 biological activity is linked to cell cycle arrest and apoptosis, ultimately leading to a strong reduction of tumor progression.…”

“…The composition and stoechiometry of the components of this complex is well described [1], where protein factors (MEPCE, LARP7) assemble around an RNA scaffold (7SK snRNA). The 7SK is by far the most abundant snRNA in the nucleus, and although it is not clear whether its biological function is limited to a structural role, this nonetheless highlights the biological importance of this complex.…”

“…This 'small' complex can bind and sequester away the P-TEFb kinase, thus forming a 'large' and catalytically inactive complex. This is mediated through direct contact between Cyclin T1 and the highly conserved motif PYNT of HEXIM [1]. This regulatory mechanism is at the heart of the control of transcription elongation and the "pause" mechanism.…”

Regulation of Mammalian Gene Expression

“…The function of P-TEFb complex is also regulated by 7SK snRNP-a small nuclear ribonucleoprotein associated with a core noncoding RNA bound with RNA binding protein HXIM (HXIM1 and 2). P-TEFb complexed with 7SK snRNP and HXIM1 are considered to functionally inactive and mammalian bromodomain protein Brd4 and human immunodeficiency virus Tat protein can replace the 7SK snRNP and make the functionally active P-TEFb complex [17,18].…”