Role of oncogenes and tumor suppressor genes in multistage carcinogenesis.
Role of oncogenes and tumor suppressor genes in multistage carcinogenesis.
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癌基因和抑癌基因在多阶段癌发生中的作用。
DOI：
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发表时间：
1994
影响因子：
6.5
通讯作者：
Wendy C. Weinberg
中科院分区：
文献类型：
--
作者：
S. H. Yuspa;A. A. Dlugosz;Christina K. Cheng;M. F. Denning;T. Tennenbaum;Adam B. Glick;Wendy C. Weinberg
作为研究皮肤癌发生的工具的分子生物学技术的引入，为调节肿瘤表型的生化途径提供了更精确的定位。这种方法已经确定了鳞癌发病机制的每个特定阶段的特征基因变化：起始、外源性促进、癌前进展和恶变。Ras基因家族的Harvey等位基因被认为是引发突变的常见位点。C-Rasha杂合激活突变占主导地位，受影响的角质形成细胞过度增殖，对终末分化信号具有抵抗力。受c-Rasha激活影响的一个重要途径是蛋白激酶C(PKC)途径，它是角质形成细胞分化的主要调节因子。酪氨酸磷酸化导致的PKCα活性增加和PKC增量抑制是角质形成细胞中RashA基因激活的表型结果。肿瘤促进剂干扰表皮的动态平衡，导致启动细胞的选择性克隆性扩张，从而产生多发性良性鳞状乳头状瘤。当表皮暴露在促进剂下时，对分化的抵抗和启动细胞的生长速度的提高赋予了生长优势。在不同的乳头状瘤中，癌前进展的频率是不同的，并且已经确定了具有高进展风险的亚群。这些高危乳头状瘤过度表达α6β4整合素，缺乏转化生长因子β1和β2肽，这两种变化与这一亚型肿瘤的高增殖率有关。将致癌基因RashA基因导入转化生长因子β1基因零突变转基因小鼠的表皮细胞，在体内检测时，恶性进展速度加快。因此，转化生长因子β基因家族的成员在致癌过程中起到了肿瘤抑制作用。在p53基因零突变的小鼠皮肤中，也发现了v-Rasha转导的角质形成细胞加速恶性进展。由TGβ1和P53缺失基因启动的角质形成细胞发生恶性转化的风险相似，表明在皮肤癌变模型中，一种常见的生长相关途径可能削弱了这些蛋白的肿瘤抑制功能。
The introduction of the techniques of molecular biology as tools to study skin carcinogenesis has provided more precise localization of biochemical pathways that regulate the tumor phenotype. This approach has identified genetic changes that are characteristic of each of the specific stages of squamous cancer pathogenesis: initiation, exogenous promotion, premalignant progression, and malignant conversion. Initiation can result from mutations in a single gene, and the Harvey allele of the ras gene family has been identified as a frequent site for initiating mutations. Heterozygous activating mutations in c-rasHa are dominant, and affected keratinocytes hyperproliferate and are resistant to signals for terminal differentiation. An important pathway impacted by c-rasHa activation is the protein kinase C (PKC) pathway, a major regulator of keratinocyte differentiation. Increased activity of PKC alpha and suppression of PKC delta by tyrosine phosphorylation contribute to the phenotypic consequences of rasHa gene activation in keratinocytes. Tumor promoters disturb epidermal homeostasis and cause selective clonal expansion of initiated cells to produce multiple benign squamous papillomas. Resistance to differentiation and enhanced growth rate of initiated cells impart a growth advantage when the epidermis is exposed to promoters. The frequency of premalignant progression varies among papillomas, and subpopulations at high risk for progression have been identified. These high-risk papillomas overexpress the alpha 6 beta 4 integrin and are deficient in transforming growth factor beta 1 and beta 2 peptides, two changes associated with a very high proliferation rate in this subset of tumors. The introduction of an oncogenic rasHa gene into epidermal cells derived from transgenic mice with a null mutation in the TGF beta 1 gene have an accelerated rate of malignant progression when examined in vivo. Thus members of the TGF beta gene family contribute a tumor-suppressor function in carcinogenesis. Accelerated malignant progression is also found with v-rasHa transduced keratinocytes from skin of mice with a null mutation in the p53 gene. The similarities in risk for malignant conversion by initiated keratinocytes from TG beta 1 and p53 null geneotypes suggest that a common, growth-related pathway may underly the tumor-suppressive functions of these proteins in the skin carcinogenesis model.
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突变的 p53 肿瘤抑制基因导致小鼠角质形成细胞对转化生长因子 β 1 产生抗性。
影响因子：
11.2
作者：
Reiss,M;Vellucci,VF;Zhou,ZL
通讯作者：
Zhou,ZL
影响因子：
8
作者：
Burns Pa;Christopher J. Kemp;Gannon Jv;David P. Lane;R. Bremner;Allan Balmain
通讯作者：
Burns Pa;Christopher J. Kemp;Gannon Jv;David P. Lane;R. Bremner;Allan Balmain
影响因子：
11.2
作者：
T. Tennenbaum;S. Yuspa;A. Grover;V. Castronovo;M. Sobel;Yoshihiko Vainada;L. M. Luca
通讯作者：
T. Tennenbaum;S. Yuspa;A. Grover;V. Castronovo;M. Sobel;Yoshihiko Vainada;L. M. Luca
DOI：
10.1073/pnas.90.3.1013
发表时间：
1993-02-01
影响因子：
11.1
作者：
RUGGERI, B;DIRADO, M;KLEINSZANTO, AJP
通讯作者：
KLEINSZANTO, AJP
小鼠皮肤乳头状瘤中非整倍性、角蛋白修饰和γ-谷氨酰转移酶表达的连续发展。
影响因子：
11.2
作者：
Aldaz,CM;Conti,CJ;Larcher,F;Trono,D;Roop,DR;Chesner,J;Whitehead,T;Slaga,TJ
通讯作者：
Slaga,TJ