HMG box transcriptional repressor HBP1 maintains a proliferation barrier in differentiated liver tissue.

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.

Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1.

In certain cancers, constitutive Wnt signaling results from mutation in one or more pathway components. The result is the accumulation and nuclear localization of beta-catenin, which interacts with the lymphoid enhancer factor-1 (LEF)/T-cell factor (TCF) family of HMG-box transcription factors, which activate important growth regulatory genes, including cyclin D1 and c-myc. As exemplified by APC and axin, the negative regulation of beta-catenin is important for tumor suppression. Another potential mode of negative regulation is transcriptional repression of cyclin D1 and other Wnt target genes. In mammals, the transcriptional repressors in the Wnt pathway are not well defined. We have previously identified HBP1 as an HMG-box repressor and a cell cycle inhibitor. Here, we show that HBP1 is a repressor of the cyclin D1 gene and inhibits the Wnt signaling pathway. The inhibition of Wnt signaling and growth requires a common domain of HBP1. The apparent mechanism is an inhibition of TCF/LEF DNA binding through a physical interaction with HBP1. These data suggest that the suppression of Wnt signaling by HBP1 may be a mechanism to prevent inappropriate proliferation.

Home care agencies & the physician customer: effective communication.

As health care moves to the outpatient setting, home care providers are in a critical position to influence physician practice patterns. An effective communication plan that facilitates the exchange of information between the home care provider and its physician customers will bridge the customer service gap and strengthen the relationship between the physician and the provider.

Home health care: the pivotal link in the creation of a new health care delivery system.

Health care reform has challenged the home care industry to reemerge as the primary site for the delivery of health care, just as it was in the beginning of the 20th century. The factors driving the growth in this industry are discussed in this article, with an overview of what can be expected in a managed care environment. An analysis of the current marketplace and predictions for the expanded role of the home health care industry in the future are outlined.