A novel role for thyroid hormone receptor beta in cellular radiosensitivity
A novel role for thyroid hormone receptor beta in cellular radiosensitivity
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DOI：
10.1269/jrr.07065
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发表时间：
2008-01-01
影响因子：
2
通讯作者：
Yamashita, Shunichi
中科院分区：
文献类型：
--
作者：
Matsuse, Michiko;Saenko, Vladimir;Yamashita, Shunichi
甲状腺激素受体（THR）广泛调控细胞生长、分化和代谢，以配体和辅因子依赖性方式发挥作用，调节组织特异性基因表达。鉴于 THR 调节的基因种类繁多，以及 THR 可能影响的细胞过程的多样性，我们探讨了 THRB（甲状腺激素受体β）在细胞放射敏感性中的作用。使用腺病毒介导的基因传递在几种细胞系中过度表达野生型和突变型 THRB，并在细胞暴露于伽马射线后检查它们的影响。野生型 THRB 降低了内源性 THRB 水平低的细胞系的克隆存活率，延缓其生长，并与辐射协同降低增殖潜力并促进细胞衰老。这些变化伴随着细胞周期蛋白依赖性激酶的p21（CDKN1A、CIP1、WAF1）和p16（CDKN2A、INK4a）抑制剂的积累以及Rb（视网膜母细胞瘤蛋白）磷酸化的减少。突变体 THRB 产生辐射防护作用，减弱辐射诱导的生长抑制和细胞衰老。结果表明 THRB 可能调节细胞放射敏感性和应激诱导的衰老。
Thyroid hormone receptors (THRs) widely govern cell growth, differentiation and metabolism acting in a ligand- and cofactor-dependent manner to modulate tissue-specific gene expression. Given a large variety of genes regulated by THRs and multiplicity of cellular processes potentially influenced by THRs, we addressed the role of THRB (thyroid hormone receptor beta) in cellular radiosensitivity. Wild-type and mutant THRB were overexpressed in several cell lines using an adenovirus-mediated gene delivery and their effects were examined after cell exposure to gamma-rays. Wild-type THRB decreased clonogenic survival of the cell lines with low levels of endogenous THRB, retarded their growth and synergized with radiation in decreasing proliferative potential and promoting cellular senescence. These changes were accompanied by the accumulation of p21 (CDKN1A, CIP1, WAF1) and p16 (CDKN2A, INK4a) inhibitors of cyclin-dependent kinases and by the decrease of Rb (retinoblastoma protein) phosphorylation. Mutant THRB produced a radioprotective effect, attenuated radiation-induced growth inhibition and cellular senescence. The results suggest that THRB may modulate cellular radiosensitivity and stress-induced senescence.