FoxM1B Protein in Stimulating Proliferation during Aging

超出提供的空间。衰老过程的一个潜在机制是细胞增殖和修复减少，以应对组织损伤。这包括DNA复制减少(S期)和进展到有丝分裂(G2/M期)，导致4NDNA含量的多倍体细胞积累，最终导致染色体不稳定和突变，导致在老年人中发现的各种疾病。随着年龄的增长，细胞增殖逐渐下降的机制尚不清楚。最近的研究表明，在衰老过程中，增殖特异性Forkhead Box M1B(FoxM1B)转录因子的表达减少与细胞增殖和细胞周期进展基因的表达减少有关。我们最近进行的肝再生研究表明，在12个月大(老年)转基因(TG)小鼠的肝细胞中保持FoxMIB的表达可以促进肝细胞的增殖，达到与年轻再生小鼠肝脏相似的水平。在老年增殖细胞中维持FoxM1B水平与促进进入S期和有丝分裂所需的许多基因的表达增加有关。综上所述，这些结果表明，FoxM1B控制着细胞增殖所必需的基因的转录网络，其表达的减少有助于细胞在衰老过程中增殖的下降。我们的长期目标是确定保持FoxM1B的表达是否会防止与年龄相关的增殖缺陷，并导致寿命延长。我们计划这样做有以下特定的目的：1)我们将有条件地删除年轻成年小鼠的FoxM1B基因，以检验在增殖细胞中FoxMIB表达消失会导致过早衰老中观察到的S期和M期缺陷进展的假说。2)我们已经创造了使用ROSA-26启动子区域在所有类型的细胞中驱动FoxM1B表达的TG小鼠。我们将使用这些小鼠来检验这样的假设，即在所有类型的细胞中保持FoxM1B水平将刺激衰老过程中的细胞增殖，并导致寿命延长。3)我们发现肿瘤抑制蛋白p19ARF(P19)抑制FoxM1B的转录活性。由于FoxM1B控制细胞周期进程基因的表达，这些结果表明p19蛋白也通过抑制FoxM1B的转录活性来介导生长停滞。我们将进一步研究FoxM1B和p19蛋白的相互作用，并使用来自rosa26-FoxM1B转基因小鼠的小鼠胚胎成纤维细胞(MEF)来验证这样的假设，即增加FOXM1B水平将推迟p19介导的复制衰老(G1停滞)。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. An underlying mechanism of the aging process involves reduced cellular proliferation and repair in response to tissue injury. This involves both diminished DNA replication (S-Phase) and progression into mitosis (G2/M block), resulting in accumulation of polyploid cells with 4N DNA content and ultimately causing chromosome instability and mutations leading to a variety of diseases found in the elderly. The mechanisms involved in the progressive decline in cellular proliferation with aging remain uncharacterized. Recent studies have shown that diminished expression of the proliferation-specific Forkhead Box M1B (FoxM1B) transcription factor is associated with reduction in both cellular proliferation and expression of cell cycle progression genes during aging. We recently performed liver regeneration studies to demonstrate that maintaining hepatocyte expression of FoxMIB in 12-month old (old-aged) transgenic (TG) mice increased hepatocyte proliferation to levels similar to those observed in young regenerating mouse liver. Maintaining FoxM1B levels in old-aged proliferating cells is associated with increased expression of numerous genes required for progression into S-phase and mitosis. Collectively, these results suggest that FoxM1B controls the transcriptional network of genes essential for cellular proliferation and that its reduced expression contributes to the decline in cellular proliferation during aging. Our long-term goal is to determine whether maintaining FoxM1B expression will prevent age-related proliferation defects and result in life span extension. We plan to do so with the following Specific Aims: 1) We will conditionally delete the FoxM1B gene in young adult mice to test the hypothesis that extinguished FoxMIB expression in proliferating cells will lead to defective S-phase and M-phase progression observed in premature aging. 2) We have created TG mice that use the Rosa-26 promoter region to drive FoxM1B expression in all cell types. We will use these mice to examine the hypothesis that maintaining FoxM1B levels in all cell types will stimulate cellular proliferation during aging and lead to life span extension. 3) We find that the tumor suppressor protein, p19ARF (p19), inhibits FoxM1B transcriptional activity. Because the FoxM1B controls expression of cell cycle progression genes, these results suggest that the p19 protein also mediates growth arrest by inhibition of FoxM1B transcriptional activity. We will further characterize the FoxM1B and p19 protein interaction and use mouse embryo fibroblasts (MEFs) from Rosa26-FoxM1B TG mice to test the hypothesis that increased FoxM1 B levels will delay p19 mediated replicative senescence (G1 arrest). PERFORMANCE SITE ========================================Section End===========================================