Involvement of Retinoblastoma Protein and HBP1 in Histone H1⁰ Gene Expression

Abstract

The histone H1 0 -encoding gene is expressed in vertebrates in differentiating cells during the arrest of proliferation. In the H1 0 promoter, a specific regulatory element, which we named the H4 box, exhibits features which implicate a role in mediating H1 0 gene expression in response to both differentiation and cell cycle control signals. For instance, within the linker histone gene family, the H4 box is found only in the promoters of differentiation-associated subtypes, suggesting that it is specifically involved in differentiation-dependent expression of these genes. In addition, an element nearly identical to the H4 box is conserved in the promoters of histone H4-encoding genes and is known to be involved in their cell cycle-dependent expression. The transcription factors interacting with the H1 0 H4 box were therefore expected to link differentiation-dependent expression of H1 0 to the cell cycle control machinery. The aim of this work was to identify such transcription factors and to obtain information concerning the regulatory pathway involved. Interestingly, our cloning strategy led to the isolation of a retinoblastoma protein (RB) partner known as HBP1. HBP1, a high-mobility group box transcription factor, interacted specifically with the H1 0 H4 box and moreover was expressed in a differentiation-dependent manner. We also showed that the HBP1-encoding gene is able to produce different forms of HBP1. Finally, we demonstrated that both HBP1 and RB were involved in the activation of H1 0 gene expression. We therefore propose that HBP1 mediates a link between the cell cycle control machinery and cell differentiation signals. Through modulating the expression of specific chromatin-associated proteins such as histone H1 0 , HBP1 plays a vital role in chromatin remodeling events during the arrest of cell proliferation in differentiating cells.During embryonic development and cell differentiation, specific transitions in gene expression are associated with chromatin remodeling (39, 58). One important aspect of these remodeling events is the synthesis of specific core and linker histones (11,30,25,33,40,51). For instance, in many organisms embryonic-and adult-type histone H1s characterize the chromatin of proliferating and differentiated cells, respectively (23). In vertebrates, the histone H1 0 gene encodes a linker histone variant which is expressed in terminally differentiated cells concomitant with the arrest of cell proliferation (23, 61). The specific role of this linker histone is not clearly established, but the timing and pattern of its expression during early embryogenesis strongly suggest a role for the protein in the organization of chromatin in arrested and differentiated cells (61). It is therefore of great interest to discover the regulatory cascade that induces the expression of this gene in differentiated cells. We believe that molecules involved in this cascade interact with different regulatory pathways, leading to a general control of chromatin remodeling during cell differentiation. Indee...

Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

“…Studies have shown that HBP1 has a key regulatory role in cell-cycle progression, cell-cycle exit, apoptosis and terminal differentiation in various tissues and cell types (Tevosian et al, 1997;Gartel et al, 1998;Shih et al, 1998;Lemercier et al, 2000), consistent with a role in tumor suppression. HBP1 gene targets include N-Myc, c-Myc, cyclin D1, myeloperoxidase, histone H1 and p47phox (Lin et al, 2001;Sampson et al, 2001;Berasi et al, 2004).…”

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

“…Most of our previous works focused on its transcriptional repression and regarded HBP1 as a novel transcriptional repressor in differentiation (Tevosian et al, 1997;Shih et al, 1998Shih et al, , 2001Lemercier et al, 2000;Xiu et al, 2003;Smith et al, 2004;Paulson et al, 2007). Only few studies have reported that HBP1 is a transcriptional activator in myeloid differentiation and transformation (Lavender et al, 1997;Yao et al, 2005).…”

“…We have previously isolated HBP1 as a retinoblastoma partner and have determined that it functions as a proliferation regulator by inhibiting oncogenic pathways as a transcriptional repressor (Lavender et al, 1997;Tevosian et al, 1997;Shih et al, 1998Shih et al, , 2001Lemercier et al, 2000;Smith et al, 2004). Recently, the HBP1 transcriptional repressor has been reported as a putative substrate for the p38 MAPK in cell-cycle arrest (Xiu et al, 2003).…”

Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer

“…B, nonparametric ANOVA analysis of HBP1 mRNA expression. HBP1 levels for normal (25)(26)(27)(28)(29)(30)(31)(32)(33) in top ), all invasive (1-23), invasive-low HBP1 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and invasive-high HBP1 (17-23) were compared by nonparametric ANOVA. Dunn's multiple comparisons test was then used.…”