FoxM1B in Preventing Age-Related Proliferation Defects

衰老过程的潜在机制涉及细胞增殖[DNA复制（s期和有丝分裂）的显著下降，导致细胞修复缺陷，以应对组织损伤，导致老年人中发现的各种疾病。随着年龄的增长，细胞增殖能力逐渐下降的机制尚未明确。叉头盒蛋白（forkhead box, Fox）是一个广泛的转录因子家族，在有翼螺旋/叉头DNA结合域中具有同源性，在调节细胞增殖、分化和寿命方面发挥重要作用。叉头盒M1B （FoxM1B）的表达在细胞增殖过程中受到刺激，但在有丝分裂后分化的细胞中其表达被抑制。然而，当最终分化的肝细胞在肝再生过程中被诱导增殖时，FoxM1B的表达在s期之前被重新激活，并在肝细胞增殖过程中持续。在再生转基因小鼠肝脏中过早表达人FoxM1B可导致肝细胞加速进入s期和有丝分裂，并与细胞周期促进基因的提前表达有关。我们最近发现，在老年转基因小鼠的肝脏再生过程中，防止FoxM1B表达的年龄相关性降低，可以使肝细胞进入s期和有丝分裂的比例增加到与年轻再生小鼠肝脏中观察到的水平相似。老年转基因小鼠再生肝脏中FoxM1B水平升高与肝细胞通过DNA复制和有丝分裂进展所需的细胞周期调控基因表达增加有关。总的来说，这些结果表明FoxM1B控制着细胞分裂和有丝分裂退出所必需的基因转录网络，有丝分裂是恢复细胞增殖所必需的。在这项拨款申请中，我们描述了扩展这些肝脏再生研究的计划，以检验在Rosa26启动子- foxm1b转基因小鼠的所有细胞类型中FoxMIB蛋白水平的增加将刺激器官损伤的细胞增殖这一假设。这些研究的长期目标是研究Rosa26-FoxM1B转基因小鼠在衰老过程中是否表现出持续的细胞增殖和寿命延长。

An underlying mechanism of the aging process involves a significant decline in cellular proliferation [DNA replication (S-Phase and mitosis) causing defective cellular repair in response to tissue injury leading to a vari8ety of diseases found in the elderly. The mechanisms involved in the progressive decline in cellular proliferation with aging remain uncharacterized. The forkhead box (Fox) proteins are an extensive family of transcription factors that share homology in the winged helix/forkhead DNA binding domain and play important roles in regulating cellular proliferation, differentiation, and longevity. Expression of Forkhead Box M1B (FoxM1B) is stimulated during cellular proliferation, but in post- mitotic differentiated cells its expression is extinguished. However, when terminally differentiated hepatocytes are induced to proliferate during liver regeneration, FoxM1B expression is reactivated prior to S-phase and sustained throughout the period of hepatocyte proliferation. Premature expression of human FoxM1B in regenerating transgenic mouse liver caused accelerated hepatocyte entry into S-phase and mitosis and was associated with earlier expression of cell cycle promoting genes. We recently showed that preventing age-related reduction of FoxM1B expression during liver regeneration in old transgenic mice increased the percentage of hepatocytes entering S-phase and mitosis to levels similar to those observed in young regenerating mouse liver. Elevated FoxM1B levels in regenerating liver of old transgenic mice are associated with increased expression of cell cycle regulatory genes required for hepatocyte to progression through DNA replication and mitosis. Collectively, these results suggest that FoxM1B controls the transcriptional network of genes essential for cell division and exit from mitosis that is required to restore cellular proliferation during aging. In this grant proposal we describe plans to extend these liver regeneration studies to examine the hypothesis that increased FoxMIB protein levels in all cell types of the Rosa26 promoter-FoxM1B transgenic mice will stimulate cellular proliferation in response to organ injury. A long-term goal of these studies ti examine whether Rosa26-FoxM1B transgenic mice display sustained cellular proliferation during aging and exhibit life span extension.