Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes
Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes
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DOI：
10.1038/sj.onc.1205404
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发表时间：
2002-05-02
期刊：
影响因子：
8
通讯作者：
Nickoloff, BJ
中科院分区：
文献类型：
--
作者：
Qin, JZ;Chaturvedi, V;Nickoloff, BJ
阳光在人表皮中的致癌作用可以通过以下方式来阻止：角质形成细胞（KC）中的短暂生长停滞和DNA光损伤的修复;通过细胞凋亡消除具有受损DNA的KC;或者通过刺激衰老开关，由此KC变得不可逆地生长停滞。使用正常人皮肤器官培养物和活的表皮等同物，我们证明在增殖基底层，通过细胞凋亡去除KCs具有快速启动（在2小时内开始）在UV光暴露后，随着UV光剂量的增加，产生逐渐更多数量的具有胸腺嘧啶二聚体的KC;涉及Apaf-1的诱导、半胱天冬酶-3的活化，并且依赖于p53活化，因为添加p53化学抑制剂阻断了凋亡反应。基底上层KC在更晚的时间点（> 8小时）发生凋亡。KCs在基底层修复DNA损伤更迅速比KCs在suprasbasal层。稳态水平的p53增加，在照射的细胞，增加是伴随着磷酸化的丝氨酸9和丝氨酸15，但不是丝氨酸6残基。相比之下，培养的KC经历自发复制衰老抵抗UV诱导的凋亡。衰老KC组成性地含有低水平的p53，其在UV暴露后既不增加也不磷酸化或乙酰化，并且具有最小的DNA结合活性，指示功能失活。此外，用DNA损伤剂阿霉素处理衰老的KCs不会导致潜在的p53激活或凋亡。当检查银屑病斑块内的KCs时，它们类似于衰老的KCs，因为它们表达p53，而不是磷酸化或乙酰化。因此，紫外线诱导人表皮KCs中的DNA损伤，触发p53激活，以及随后涉及不同细胞层和动力学的凋亡。然而，在衰老的KCs和银屑病斑块中所见的p53活化的缺乏与KCs对UV诱导的细胞凋亡的相对抗性有关。总之，KCs对凋亡的敏感性和抗性不仅取决于表皮各层内的位置和p53的水平，还可能涉及通过翻译后修饰的p53激活。
The carcinogenic effects of sunlight in human epidermis may be thwarted by either: transient growth arrest and repair of DNA photodamage in keratinocytes (KCs); elimination of KCs with damaged DNA via apoptosis; or by stimulating a senescence switch whereby KCs become irreversibly growth arrested. Using normal human skin organ cultures and living epidermal equivalents, we demonstrate that in the proliferative basal layer, removal of KCs via apoptosis had a rapid onset (beginning within 2 h) following UV-light exposure generating progressively greater numbers of KCs with thymine dimers as the dose of UV-light was increased; involved induction of Apaf-1, activation of caspase-3, and was dependent on p53 activation as addition of a p53 chemical inhibitor blocked the apoptotic response. Suprabasal layer KCs underwent apoptosis at much later time points (> 8 h). KCs in the basal layer repaired DNA damage more rapidly than KCs in suprabasal layers. Steady state levels of p53 increased in irradiated cells, and the increase was accompanied by phosphorylation of serine 9 and serine 15, but not serine 6 residues. By contrast, cultured KCs undergoing spontaneous replicative senescence were resistant to UV-induced apoptosis. Senescent KCs constitutively contained low levels of p53, which were neither increased nor phosphorylated or acetylated after UV-exposure and possessed minimal DNA binding activity, indicative of functional inactivation. Furthermore, treatment of senescent KCs with DNA damaging agent adriamycin did not result in activation of latent p53 or apoptosis. When KCs within psoriatic plaques were examined, they resembled senescent KCs in that they expressed p53, which was not phosphorylated or acetylated. Thus, UV-light induces DNA damage in human epidermal KCs triggering p53 activation, and subsequent apoptosis involving distinct cell layers and kinetics. However, the lack of p53 activation as seen in senescent KCs and psoriatic plaques, is associated with a relative resistance of KCs to UV-induced apoptosis. In conclusion, the sensitivity and resistance of KCs to apoptosis depends not only on the location within various layers of epidermis and levels of p53, but may also involve p53 activation via post-translational modifications.