Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
J Biol Chem. 2010 Aug 6;285(32):24477-86. doi: 10.1074/jbc.M109.100222. Epub 2010 Jun 7.
Failure of the functional pancreatic beta-cell mass to expand in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is important for beta-cell proliferation in adult animals. In rat pancreatic beta-cell lines (RIN5F), treatment with 100 nM thyroid hormone (triiodothyronine, T(3)) enhances cell proliferation. This result suggests that T(3) is required for beta-cell proliferation or replication. To identify the role of thyroid hormone receptor alpha (TR(alpha)) in the processes of beta-cell growth and cell cycle regulation, we constructed a recombinant adenovirus vector, AdTR(alpha). Infection with AdTR(alpha) to RIN5F cells increased the expression of cyclin D1 mRNA and protein. Overexpression of the cyclin D1 protein in AdTR(alpha)-infected cells led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway, along with cell cycle progression and cell proliferation following treatment with 100 nM T(3). Conversely, lowering cellular cyclin D1 by small interfering RNA knockdown in AdTR(alpha)-infected cells led to down-regulation of the cyclin D1/CDK/Rb/E2F pathway and inhibited cell proliferation. Furthermore, in immunodeficient mice with streptozotocin-induced diabetes, intrapancreatic injection of AdTR(alpha) led to the restoration of islet function and to an increase in the beta-cell mass. These results support the hypothesis that liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass during postnatal development. Thus, liganded TR(alpha) may be a target for therapeutic strategies that can induce the expansion and regeneration of beta-cells.
功能性胰腺 β 细胞质量未能响应代谢需求的增加而扩张是 2 型糖尿病的一个标志。谱系追踪研究表明，现有 β 细胞的复制对于成年动物的 β 细胞增殖很重要。在大鼠胰腺 β 细胞系 (RIN5F) 中，用 100 nM 甲状腺激素 (三碘甲状腺原氨酸，T(3)) 处理可增强细胞增殖。这一结果表明 T(3)是 β 细胞增殖或复制所必需的。为了确定甲状腺激素受体 α (TR(alpha)) 在 β 细胞生长和细胞周期调控过程中的作用，我们构建了重组腺病毒载体 AdTR(alpha)。用 AdTR(alpha)感染 RIN5F 细胞可增加细胞周期蛋白 D1 mRNA 和蛋白的表达。在 AdTR(alpha)感染的细胞中过表达 cyclin D1 蛋白可激活 cyclin D1/cyclin 依赖性激酶/视网膜母细胞瘤蛋白/E2F 通路，随后用 100 nM T(3)处理可导致细胞周期进程和细胞增殖。相反，用 AdTR(alpha)感染的细胞中的小干扰 RNA 敲低降低细胞 cyclin D1 可下调 cyclin D1/CDK/Rb/E2F 通路并抑制细胞增殖。此外，在链脲佐菌素诱导糖尿病的免疫缺陷小鼠中，胰腺内注射 AdTR(alpha)可恢复胰岛功能并增加 β 细胞质量。这些结果支持以下假说：配体结合的 TR(alpha)在β 细胞复制和出生后发育过程中 β 细胞质量的扩大中发挥关键作用。因此，配体结合的 TR(alpha)可能是一种治疗策略的靶点，该策略可以诱导β 细胞的扩张和再生。
