p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice.
p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice.
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DOI：
10.1158/0008-5472.can-08-4455
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发表时间：
2009-06
期刊：
影响因子：
11.2
通讯作者：
Eva M Schindler;A. Hindes;Erin L Gribben;Carole J. Burns;Yan Yin;Meei-Hua Lin;Robert J. Owen;G. Longmore;G. Kissling;J. Arthur;T. Efimova
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文献类型：
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作者：
Eva M Schindler;A. Hindes;Erin L Gribben;Carole J. Burns;Yan Yin;Meei-Hua Lin;Robert J. Owen;G. Longmore;G. Kissling;J. Arthur;T. Efimova
激活Ras突变发生在大部分人类肿瘤中。然而，Ras诱导的肿瘤形成中涉及的信号通路仍然不完全清楚。丝裂原活化蛋白激酶途径是研究得最好的Ras效应途径之一。p38丝裂原活化蛋白激酶亚型是关键生物学过程的重要调节剂，包括细胞增殖、分化、存活、炎症、衰老和肿瘤发生。然而，具体在体内的贡献个别p38亚型皮肤肿瘤的发展尚未阐明。最近的研究表明，p38 δ，p38家族成员，作为表皮角质形成细胞分化和存活的重要调节因子。在本研究中，我们通过对p38 δ基因敲除小鼠进行两阶段7，12-二甲基苯并蒽/12-O-十四酰基佛波醇-13-乙酸酯化学皮肤致癌实验，评估了p38 δ缺陷对体内皮肤肿瘤发生的影响。我们报道了缺乏p38 delta基因的小鼠对7，12-二甲基苯蒽/12-O-十四烷酰佛波醇-13-乙酸酯诱导的皮肤乳头状瘤的发展表现出显著的抵抗力，与野生型小鼠相比，潜伏期增加，肿瘤的发生率、多样性和大小大大降低。我们的数据表明，p38缺失小鼠皮肤癌易感性降低的潜在机制涉及与异常信号传导相关的增殖反应缺陷，这两个主要的促进转化途径是：细胞外信号调节激酶1/2-激活蛋白1和信号转导和转录激活因子3。这些发现强烈地表明p38 δ在促进表皮中的细胞增殖和肿瘤发展中的体内作用，并且可能对皮肤癌具有治疗意义。
Activating Ras mutations occur in a large portion of human tumors. Yet, the signaling pathways involved in Ras-induced tumor formation remain incompletely understood. The mitogen-activated protein kinase pathways are among the best studied Ras effector pathways. The p38 mitogen-activated protein kinase isoforms are important regulators of key biological processes including cell proliferation, differentiation, survival, inflammation, senescence, and tumorigenesis. However, the specific in vivo contribution of individual p38 isoforms to skin tumor development has not been elucidated. Recent studies have shown that p38delta, a p38 family member, functions as an important regulator of epidermal keratinocyte differentiation and survival. In the present study, we have assessed the effect of p38delta deficiency on skin tumor development in vivo by subjecting p38delta knockout mice to a two-stage 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate chemical skin carcinogenesis protocol. We report that mice lacking p38delta gene exhibited a marked resistance to development of 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin papillomas, with increased latency and greatly reduced incidence, multiplicity, and size of tumors compared with wild-type mice. Our data suggest that the underlying mechanism for reduced susceptibility to skin carcinogenesis in p38delta-null mice involves a defect in proliferative response associated with aberrant signaling through the two major transformation-promoting pathways: extracellular signal-regulated kinase 1/2-activator protein 1 and signal transducer and activator of transcription 3. These findings strongly suggest an in vivo role for p38delta in promoting cell proliferation and tumor development in epidermis and may have therapeutic implication for skin cancer.