Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha.
Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha.
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发表时间：
1996-10
期刊：
影响因子：
11.2
通讯作者：
D. Greenhalgh;Xiaojing Wang;L. Donehower;D. Roop
中科院分区：
文献类型：
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作者：
D. Greenhalgh;Xiaojing Wang;L. Donehower;D. Roop
为了研究p53肿瘤抑制基因缺失在多阶段癌变小鼠模型中的作用，将通过基因靶向（p53 -/-）产生的p53敲除小鼠与表达v-rasHa的转基因小鼠交配。（HK1.ras）、v-fos（HK1.fos）或人转化生长因子α + HK1.TGF α）。表达野生型p53等位基因（p53 +/+）或p53敲除等位基因（p53+/-）的半合子的HK 1-p53转基因后代与亲本HK 1系相同，并表现出新生儿表皮增生或成人伤口相关增生，以及自发性或12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的良性乳头状瘤。与p53-/-交配并没有导致预期的成年人肿瘤发生。相反，尽管p53缺失的HK1.ras或HK1.TGF α转基因小鼠（分别为HK 1.ras-p53-/-和HK1.TGF α-p53-/-）保留了新生儿表皮增生表型，但在成年小鼠中，自发性和TPA促进的乳头状瘤形成被阻断。同样，伤口相关的表皮增生/角化过度，成年HK1.fos表型的标志，在HK 1.fos-p53 -/-小鼠中完全不存在。组织学，免疫荧光，和溴脱氧尿苷标记分析的新生儿或成人表皮HK 1-p53转基因型+/+，+/-，和-/-p53显示没有明显的差异，形态，角化细胞分化标志物的表达，或有丝分裂指数归因于p53损失。为了确定乳头状瘤的反常缺失是否以p53靶基因的上调为中心，在TPA促进实验中检查了WAF 1/CIP 1/p21 RNA表达水平。在所有HK 1-p53转基因基因型中，无论p53状态如何，TPA促进WAF 1/CIP 1/p21表达增加。然而，在HK 1-p53无效基因型中，虽然观察到TPA诱导的、不依赖于p53的WAF 1/CIP 1/p21表达，但表达的大幅增加与所观察到的反常肿瘤发生阻滞无关。这些数据表明，表皮是有点抵抗p53损失的肿瘤效应，可能拥有几个补偿系统。或者，可能需要p53表达来响应TPA或小鼠表皮中的伤口促进刺激。
To investigate the effect of p53 tumor suppressor gene loss in the mouse skin model of multistage carcinogenesis, p53 knockout mice, generated by gene targeting (p53 -/-), were mated to transgenic mice expressing v-rasHa (HK1.ras), v-fos (HK1.fos), or human transforming growth factor alpha+HK1.TGFalpha) exclusively in the epidermis, by means of a keratin K1-based targeting vector (HK1). HK1-p53 transgenic progeny expressing wild-type p53 alleles (p53 +/+) or hemizygous for the p53 knockout allele (p53+/-) were identical to parental HK1 lines and exhibited neonatal epidermal hyperplasia or wound-associated hyperplasia in adults, together with spontaneous or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced benign papillomas. Mating to p53-/- did not lead to the expected tumorigenesis in adults. Instead, whereas HK1.ras or HK1.TGFalpha transgenic mice null for p53 (HK1.ras-p53-/- and HK1.TGFalpha-p53-/-, respectively) retained the neonatal epidermal hyperplasia phenotype, in adults, spontaneous and TPA-promoted papilloma formation was blocked. Similarly, wound-associated epidermal hyperplasia/hyperkeratosis, a hallmark of adult HK1.fos phenotypes, was completely absent in HK1.fos-p53 -/- mice. Histological, immunofluorescence, and bromodeoxyuridine labeling analysis of neonatal or adult epidermis in HK1-p53 transgenic genotypes +/+, +/-, and -/- for p53 revealed no obvious differences in morphology, expression of keratinocyte differentiation markers, or mitotic index attributed to p53 loss. To determine whether the paradoxical absence of papillomas centered on up-regulation of p53 target genes, WAF1/CIP1/p21 RNA expression levels were examined in TPA promotion experiments. WAF1/CIP1/p21 expression increased in response to TPA promotion in all HK1-p53 transgenic genotypes regardless of p53 status. However, in HK1-p53 null genotypes, although TPA-induced, p53-independent WAF1/CIP1/p21 expression was observed, no large increase in expression was associated with the observed paradoxical tumorigenesis block. These data suggest that epidermis is somewhat resistant to the neoplastic effects of p53 loss, possibly possessing several compensatory systems. Alternatively, there may be a requirement forp53 expression in response to TPA or a wound-promotion stimulus in mouse epidermis.