The transcriptional regulatory function of p53 is essential for suppression of mouse skin carcinogenesis and can be dissociated from effects on TGF-beta-mediated growth regulation.
The transcriptional regulatory function of p53 is essential for suppression of mouse skin carcinogenesis and can be dissociated from effects on TGF-beta-mediated growth regulation.
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DOI：
10.1002/path.2600
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发表时间：
2009-10
影响因子：
7.3
通讯作者：
Weinberg, Wendy C.
中科院分区：
文献类型：
--
作者：
Ponnamperuma, Roshini M.;King, Kathryn E.;Elsir, Tamador;Glick, Adam B.;Wahl, Geoffrey M.;Nister, Monica;Weinberg, Wendy C.
p53的转录调控对于p53介导的肿瘤抑制是至关重要的;然而，p53介导的反式激活已经与p53介导的生物学过程（包括细胞凋亡、DNA修复和分化）分离。我们比较了突变等位基因p53 QS-val 135与p53完全丧失的效应，p53 QS-val 135在氨基末端含有双突变，消除了反式激活活性，在氨基酸135处含有修饰，部分影响DNA结合。我们应用与上皮肿瘤发生相关的体外终点和肿瘤表型的体内测定来评估p53介导的转录调控的丧失是否是p53−/−/v-rasHa过表达的角质形成细胞的恶性表型的基础。通过成纤维细胞和分化中的角质形成细胞中的报告基因测定证实了p53 QS-val 135的反式激活缺陷。Ras癌基因诱导的衰老在p53 QS-val 135/QS -val 135和p53−/−角质形成细胞中均消失。类似地，p53 QS-val 135/QS -val 135与p53−/−一样，与v-rasHa合作促进恶性转化。在p53 QS-val 135/QS-val 135角质形成细胞中产生的肿瘤显示出强的核p53表达;因此，p53 QS-val 135等位基因得以维持，并且在这些肿瘤中p21 waf 1的缺失支持了所表达的p53 QS突变蛋白的反式激活功能的缺陷。p53 QS-val 135等位基因没有赋予显性阴性表型，因为p53+/QS -val 135角质形成细胞响应于v-rasHa表达而正常衰老并形成良性肿瘤。虽然p53−/−角质形成细胞对TGF-β的反应减弱，但p53 QS-val 135/QS-val 135和p53+/+角质形成细胞的反应相当，表明在最大化TGF-β介导的生长调节中对p53的需求与其反式激活结构域无关，并且角质形成细胞对TGF-β的反应能力不足以抑制该模型中的恶性表型。此外，TGF-β增强角质形成细胞系中p53-TGF-β双重应答报告基因的p53 QS诱导的活化。这些研究结果支持p53介导的转录调控在抑制ras诱导的皮肤肿瘤引起的恶性肿瘤中的重要作用，与先前在其他器官中自发致癌的研究结果一致，并突出了衰老对体内肿瘤抑制的潜在重要性。
Transcriptional regulation by p53 is critical for p53-mediated tumour suppression; however, p53-mediated transactivation has been dissociated from p53-mediated biological processes including apoptosis, DNA repair, and differentiation. We compared the effects of a mutant allele, p53QS –val135, containing a double mutation in the amino-terminus abrogating transactivation activity and a modification at amino acid 135 partially affecting DNA binding, to complete loss of p53. We applied in vitro endpoints correlated with epithelial tumourigenesis and an in vivo assay of tumour phenotype to assess whether loss of p53-mediated transcriptional regulation underlies the malignant phenotype of p53−/−/v-rasHa-overexpressing keratinocytes. Transactivation deficiency of p53QS-val135 was confirmed by reporter gene assays in fibroblasts and differentiating keratinocytes. Ras oncogene-induced senescence was lost in both p53QS –val135/QS –val135 and p53−/− keratinocytes. Similarly, p53QS –val135/QS –val135, like p53−/−, cooperated with v-rasHa to enhance malignant conversion. The tumours arising in p53QS –val135/QS –val135 keratinocytes displayed strong nuclear p53 expression; thus, the p53QS –val135 allele was maintained and the deficient transactivation function of the expressed p53QS mutant protein was supported by absence of p21waf1 in these tumours. The p53QS –val135 allele did not confer a dominant-negative phenotype, as p53+/QS –val135 keratinocytes senesced normally in response to v-rasHa expression and formed benign tumours. While p53−/− keratinocytes displayed diminished response to TGF-β, p53QS –val135/QS –val135 and p53+/+ keratinocytes responded equivalently, indicating that the requirement for p53 in maximizing TGF-β-mediated growth regulation is independent of its transactivation domain and that the ability of keratinocytes to respond to TGF-β is insufficient to suppress the malignant phenotype in this model. Furthermore, TGF-β enhances p53QS-induced activation of a dual p53-TGF-β responsive reporter in a keratinocyte cell line. These findings support an essential role for p53-mediated transcriptional regulation in suppressing malignancies arising from ras-induced skin tumours, consistent with previous findings in spontaneous carcinogenesis in other organs, and highlight the potential importance of senescence for tumour suppression in vivo.
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影响因子：
30.8
作者：
Dumont, P;Leu, JIJ;Murphy, M
通讯作者：
Murphy, M
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
8
作者：
Nistér, M;Tang, MJ;Wahl, GM
通讯作者：
Wahl, GM
DOI：
10.1073/pnas.0706764105
发表时间：
2008-01-29
影响因子：
11.1
作者：
Johnson, Thomas M.;Meade, Kristin;Attardi, Laura D.
通讯作者：
Attardi, Laura D.