Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis.
Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis.
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DOI：
10.1016/j.ijrobp.2008.09.036
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发表时间：
2009-02-01
影响因子：
7
通讯作者：
Limesand, Kirsten H.
中科院分区：
文献类型：
--
作者：
Avila, Jennifer L.;Grundmann, Oliver;Burd, Randy;Limesand, Kirsten H.
头颈部癌症的放射治疗在唾液腺中引起不良的继发性副作用，并导致患者生活质量下降。先前在腮腺唾液腺中的体内研究表明，有针对性的头部和颈部照射导致磷酸化p53（丝氨酸18）和细胞凋亡的显着增加，这是抑制在转基因小鼠表达的Akt 1（myr-Akt 1）的组成型活性突变体。转基因和基因敲除小鼠模型暴露于辐射和p53介导的转录，细胞凋亡和唾液腺功能障碍进行了分析。我们报告，促凋亡p53靶基因p53和Bax诱导腮腺唾液腺的小鼠在治疗性放射治疗后的早期时间点。这种剂量依赖性诱导需要p53的表达，因为在p53−/−小鼠中没有观察到辐射诱导的p53和Bax的表达。辐射还以剂量依赖性方式诱导腮腺中的细胞凋亡，这是p53依赖性的。此外，p53的表达是辐射后唾液功能的急性和慢性丧失所必需的。相比之下，p53−/−小鼠在辐射暴露后不会诱导细胞凋亡并保留唾液功能。这些结果表明，治疗性头颈部照射后唾液腺中的细胞凋亡是由p53介导的，并且对应于体内唾液腺功能障碍。
Radiation therapy for head and neck cancer causes adverse secondary side effects in the salivary glands and results in diminished quality of life for the patient. A previous in vivo study in parotid salivary glands demonstrated that targeted head and neck irradiation resulted in marked increases in phosphorylated p53 (serine18) and apoptosis, which was suppressed in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1). Transgenic and knockout mouse models were exposed to irradiation and p53-mediated transcription, apoptosis, and salivary gland dysfunction were analyzed. We report that the pro-apoptotic p53 target genes PUMA and Bax are induced in parotid salivary glands of mice at early time points following therapeutic radiation. This dose-dependent induction requires expression of p53 as no radiation-induced expression of PUMA and Bax is observed in p53−/− mice. Radiation also induces apoptosis in the parotid gland in a dose dependent manner, which is p53-dependent. Furthermore, expression of p53 is required for the acute and chronic loss of salivary function following irradiation. In contrast, p53−/− mice do not induce apoptosis and preserve salivary function after radiation exposure. These results indicate that apoptosis in the salivary glands following therapeutic head and neck irradiation is mediated by p53 and corresponds to salivary gland dysfunction in vivo.
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影响因子：
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