HMG Box Transcriptional Repressor HBP1 Maintains a Proliferation Barrier in Differentiated Liver Tissue

Abstract

We previously isolated HBP1 as a target of the retinoblastoma (RB) and p130 family members and as the first of the HMG box transcriptional repressors. Our subsequent work demonstrated that HBP1 coordinates differentiation in cell culture models. In the present study, we show that HBP1 regulates proliferation in a differentiated tissue of an animal. Using transgenic mice in which HBP1 expression was specifically increased in hepatocytes under control of the transthyretin promoter, we determined the impact of HBP1 on synchronous cell cycle reentry following partial hepatectomy. Modest overexpression of HBP1 yielded a detectable cell cycle phenotype. Following a mitogenic stimulus induced by two-thirds partial hepatectomy, mice expressing the HBP1 transgene showed a 10-to 12-h delay in progression through G 1 to the peak of S phase. There was a concomitant delay in mid-G 1 events, such as the induction of cyclin E. While the delay in G 1 and S phases correlated with the slight overexpression of transgenic HBP1, the level of the endogenous HBP1 protein itself declined in S phase. In contrast, the onset of the immediate-early response following partial hepatectomy was unchanged in HBP1 transgenic mice. This observation indicated that the observed delay in S phase did not result from changes in signaling pathways leading into the G 0 -to-G 1 transition. Finally, transgenic mice expressing a mutant HBP1 lacking the N-terminal RB interacting domain showed a stronger S-phase response following partial hepatectomy. These results provide the first evidence that HBP1 can regulate cell cycle progression in differentiated tissues.

Cyclin D1 Inhibits Peroxisome Proliferator-activated Receptor γ-mediated Adipogenesis through Histone Deacetylase Recruitment

“…The repression of ligandinduced receptor activation was previously reported for corepressor complexes coordinated by the SMRT/HDAC1-associated repressor protein (SHARP) (34), the transcription intermediary factor TIF1 (35), and the metastases-associated protein 1 co-repressor MTA (36). The binding of cyclin D1 to HDAC1 and the inhibition of PPAR␥-mediated differentiation by cyclin D1 is also consistent with previous studies on the role of HDAC1 in regulation of nuclear receptor function (30).…”

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).…”

“…Then, cells were incubated overnight at 37 1C with freshly prepared SA-b-gal stain solution (1mg/ml X-gal, 40 mM citric acid/sodium phosphate (pH 6.0), 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, 150 mM NaCl, 2 mM MgCl 2 ). At least 300 cells were counted in randomly chosen fields (Shih et al, 2001).…”

“…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).…”

Differential regulation of cyclins D1 and D3 in hepatocyte proliferation

“…16 In several models of impaired liver regeneration, cyclin D1 expression after PH is diminished. [18][19][20][21][22] Cyclin D1 is dependent on mitogen stimulation in cultured hepatocytes, and its induction during late G1 phase coincides with progression through the late G1 restriction point, at which time the cell becomes committed to proceed with replication even if mitogens are withdrawn. 23,24 Furthermore, transfection of hepatocytes in culture with cyclin D1 promotes cell cycle progression in the absence of mitogen, or in the presence of growth-inhibitory extracellular matrix (ECM) conditions.…”