Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms

Abstract

Stra13 is a transcriptional repressor related within its basic helixloop-helix domain with the Drosophila Hairy, Enhancer of Split, and the mouse Hes1 proteins that interact with the corepressor Groucho. Because Stra13 lacks the conserved WRPW motif for interaction with Groucho, we examined the function and mechanism of transcriptional repression mediated by Stra13 that exhibits several distinctive features. Here, we report that Stra13 expression is closely associated with cell growth arrest induced by several triggers such as retinoic acid and trichostatin A (TSA; a specific histone deacetylase inhibitor) as well as by serum starvation. Stra13 expression is transcriptionally repressed and maintained at a low level in cells through a negative autoregulatory mechanism that is brought about by its interaction with the corepressor histone deacetylase (HDAC1). This interaction requires the Stra13 C-terminal domain containing three ␣-helices, which are also functionally critical to its repressive activity. Thus, inhibition of HDAC activity by TSA abrogates Stra13-mediated repression of its promoter, resulting in induction of Stra13 expression that is coincident with TSA-induced growth arrest. Further, once induced, Stra13 strongly represses the expression of the cell proliferationassociated gene c-Myc through an HDAC1-independent pathway that involves its interaction with the basal transcription factor TFIIB. Our studies indicate that Stra13 may play a key role in signaling pathways that lead to growth arrest and terminal differentiation by repression of target genes via HDAC-dependent and HDAC-independent mechanisms. T ranscription factors of the basic helix-loop-helix (bHLH) family are important regulators of cellular growth, differentiation, and apoptosis (1). Stra13 is a novel bHLH gene (2) that exhibits the highest sequence identity in the bHLH domain with the Drosophila Hairy (H), Enhancer of Split [E(Spl)], and mouse Hes1 proteins (3). Members of this subfamily bind to an N-box sequence element and act as transcriptional repressors by recruiting the corepressor Groucho through a highly conserved ''WRPW'' motif (4). Outside the bHLH domain, Stra13 shares no significant identity with known proteins and is characterized by three putative ␣-helices in its C terminus. Although Stra13 does not bind the N-box element, it does exhibit a strong transcriptional repression activity that is mediated through the ␣-helices (2). Moreover, unlike E(Spl), Hairy, and Hes, Stra13 lacks a WRPW motif, suggesting that it may mediate transcriptional repression by interaction with corepressors other than Groucho.Recent studies have provided molecular evidence that modification of chromatin structure by histone deacetylation is an important mechanism in controlling gene transcription. Several transcriptional repressors such as YY-1, RB, and CBF-1 interact directly with histone deacetylases (HDAC), whereas nuclear hormone receptors, Mad, and PLZF are linked indirectly to HDAC through additional components [silencing mediator of retinoi...

Differentiated Embryo Chondrocyte 1 (DEC1) Represses PPARγ2 Gene through Interacting with CCAAT/Enhancer Binding Protein β (C/EBPβ)

“…Although a nonspecific band is detected at 55 kDa which corresponds to the molecular weight of both IgG and flag-tagged HDAC1, more protein is detected in the immuneprecipitant from the cells transfected with myc-tagged DEC1. This result confirmed the previous finding that DEC1 interacts with HDAC1 (Sun and Taneja, 2000). Then, we tested whether the interaction between DEC1 and HDAC1 is maintained in MDI treated NIH3T3/Cβ cells.…”

“…We presumed that DEC1 were indirectly recruited on the PPARγ2 promoter by interacting with C/EBPβ and/or other putative proteins on the PPARγ2 promoter. The previous finding that DEC1 can interact with histone deacetylase 1 (HDAC1), suggests that DEC1 on the PPARγ2 promoter can recruit HDAC1, which is involved in deacetylation of histones (Sun and Taneja, 2000). As shown in Fig.…”

“…However, hypoxia-induced DEC1, if any, may not be recruited on PPARγ2 promoter through interacting with promoter-bound C/EBPβ, since hypoxia prevents C/EBPβ from binding to PPARγ2 promoter by HIF-1α independent mechanism (Park and Park, 2010). The previous findings that DEC1 is induced by many other signals involved in mammalian cell differentiation, cell cycle, circadian rhythm and carcinogenesis suggest that DEC1 is one of the mediators which reset the pattern of PPARγ2 expression in response to not only hypoxia but also the other signals (Bhawal et al, 2011;Kovac et al, 2009;Noshiro et al, 2005;Sun and Taneja, 2000).…”

Characterization of Peripheral Circadian Clocks in Adipose Tissues

“…Although we observed similar oscillations in liver, we were not able to detect circadian expression of Stra13 in adipose tissues. These inconsistencies may stem from the relatively low expression of Stra13 in these tissues; STRA13 exerts an autologous negative feedback control on its own promoter transcription, thus keeping the gene expression low (37).…”

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

“…STRA13 is expressed in differentiating embryonic and adult tissues (Boudjelal et al, 1997;Shen et al, 1997), responds to a broad range of growth stimuli (Shen et al, 2001;Zawel et al, 2002), and serves as a key regulator of lymphoid cell development and activation (Sun et al, 2001;Seimiya et al, 2004). Transcriptional repression activity of STRA13 can be established through direct DNA binding to the E-box (St-Pierre et al, 2002;Zawel et al, 2002;Azmi et al, 2003) via its basic region, or through indirect involvement in transcriptional modulation via interaction with multiple transcription factors, such as USF (Dhar and Taneja, 2001), TBP and TFIIB (Boudjelal et al, 1997), MyoD (Azmi et al, 2003), and MSP58 (Ivanova et al, 2005), or with the HDAC complex components (Sun and Taneja, 2000). Recently, our data on the interaction of STRA13 with STAT3 (Ivanova et al, 2004) implicated STRA13 in the JAK/STAT signal transduction pathway that plays a central role in regulation of the immune system (Bach et al, 1997;Shuai and Liu, 2003).…”