细胞衰老过程中HuR与HuB/D对端粒酶活性的竞争性调控作用

RNA结合蛋白ELAV1（HuR）可通过结合TERC维持端粒酶活性。除HuR外，神经组织还存在其它三种ELAV家族基因（HuB，HuC，HuD）表达, 但后三个ELAV家族成员对端粒酶活性的调控作用与机制有待探讨。前期研究显示， 1）HuB和HuD（HuB/D）均可结合TERC，拮抗HuR与TERC的相互作用，抑制神经细胞端粒酶活性；2）HuB和HuD代偿性（相互补偿）调节神经细胞端粒酶活性和端粒长度。我们推测，HuR与HuB/D通过TERC竞争性拮抗调控端粒酶活性，影响神经细胞生长与衰老。本研究拟进一步探讨HuR与HuB/D竞争性调控端粒酶活性的分子机制，阐明这种竞争性调控在神经母细胞瘤细胞生长与衰老过程中的意义，并在病人神经母细胞瘤组织中分析HuR、HuB/D与端粒酶活性的关联性。这些研究将从新角度揭示神经肿瘤细胞端粒酶活性的维持机制，也可为临床相关干预措施提供实验依据。

RNA binding protein ELAV1 (HuR) has been demonstrated to maintain the telomerase activity via interaction with TERC. By contrast with the ubiquitous expression of HuR, the other three members of ELAV family (neuronal ELAV proteins: HuB, HuC, and HuD) are predominantly confined to nervous tissues. However, whether neuronal ELAV proteins could similarly regulate telomerase and the latent role of co-regulation are obscured. Our preliminary work suggested that 1) HuB and HuD (HuB/D) compete with HuR for interaction with TERC thus repressing telomerase activity, 2) HuB reconciles with HuD in regulating telomerase activity and telomere length. It is hypothesized that HuR and HuB/D regulate telomerase activity in an antagonistic manner through competitive binding to TERC thereby influencing neurogenic cell proliferation and senescence. We are further to explore the mechanism of HuR and HuB/D contending for telomerase activity modulation and to figure out the impact of competitive regulation on neuroblastoma cellular senescence and tumor progression. Moreover, neuroblastoma specimens procured from patients would be utilized to authenticate the associations among HuR, HuB/D, and telomerase activity. These work should shed new light on telomerase maintenance of neurologic tumors as well as provide some experimental evidences for future clinical interventions.