Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.13.3 (histidine kinase)
 2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To develop an in vivo model for studying the role of the p53 tumor suppressor in skin carcinogenesis, a murine p53(172H) mutant (equivalent to human p53(175H)) was expressed in the epidermis of transgenic mice, utilizing a targeting vector based on the human keratin 1 gene (HK1.p53m). HK1.p53m mice developed normally and did not exhibit an obvious epidermal phenotype or develop spontaneous tumors. However, these mice demonstrated an increased susceptibility to a two-stage chemical carcinogenesis protocol, with the rate of formation and number of papillomas being dramatically increased as compared to non-transgenic controls. The majority of papillomas in control mice regressed after termination of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, whereas p53m papillomas progressed to carcinomas and metastases. In addition, more advanced malignancy, i.e., undifferentiated spindle cell carcinomas, were exclusively observed in p53m mice. Increased bromodeoxyuridine (BrdU) labeling, accompanied by decreased expression of p21, was observed in HK1.p53m papillomas. In situ examination of centrosomes in HK1.p53m papillomas also revealed marked abnormalities, with 75% of the cells containing > or = 3 centrosomes/cell, whereas centrosome numbers in papillomas from control animals remained normal. These data suggest that the accelerated tumorigenesis observed in chemically-treated p53m mice is most likely due to increased genomic instability resulting from an inhibition of G1 arrest and abnormal amplification of centrosomes.
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PMID:Expression of a p53 mutant in the epidermis of transgenic mice accelerates chemical carcinogenesis. 967 12

We previously developed a transgenic mouse model that expresses in the epidermis a murine p53172R-->H mutant (p53m) under the control of a human keratin-1-based vector (HK1.p53m). In contrast to mice with wild-type p53 and p53-knockout mice, HK1.p53m mice exhibit increased susceptibility to chemical carcinogenesis, with greatly accelerated benign papilloma formation, malignant conversion, and metastasis. In the study presented here, we examined the expression pattern of several differentiation markers and observed that p53m tumors exhibited a less differentiated phenotype than tumors elicited in non-transgenic mice. Metastasis in p53m tumors was also associated with a poorly differentiated phenotype. To determine whether genomic instability was associated with a putative gain-of-function role for this p53m, in situ examination of centrosomes was performed in HK1.p53m and equivalent p53-null papillomas. In contrast to HK1.p53m papillomas, which had centrosome abnormalities at high frequencies (75% of cells contained more than three centrosomes/cell), p53-null tumors exhibited few abnormal centrosomes (4% of cells contained more than three centrosomes/cell). To determine whether angiogenesis played a role in the rapid progression of p53m tumors, the expression of vascular endothelial growth factor, a promoter of angiogenesis, and thrombospondin-1, an inhibitor of angiogenesis, was examined in tumors derived from either p53m or p53-knockout mice. Regardless of their p53 status (wild type, p53m, p53-/-), all of the papillomas exhibited similar levels of vascular endothelial growth factor expression and decreased expression of thrombospondin-1 as did normal epidermis. In addition, tumors from different p53 genotypes showed a similar density of blood vessels. Because p53 status did not appear to play an overt role in angiogenesis, these data suggest that p53m accelerates tumorigenesis primarily by exerting a gain of function associated with genomic instability.
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PMID:Analysis of centrosome abnormalities and angiogenesis in epidermal-targeted p53172H mutant and p53-knockout mice after chemical carcinogenesis: evidence for a gain of function. 983 79

Nonmelanoma skin cancer (NMSC) is the most frequently diagnosed cancer in the United States. Deregulation of bcl-2 and ras family members is commonly observed in NMSC. It has been previously demonstrated that simultaneous bcl-2 and Ha-ras gene expression in keratinocytes results in disordered differentiation and resistance to cell death induced by ultraviolet (UV) radiation. It was, therefore, interest to assess the extent of cooperation between bcl-2 and Ha-ras during multistep skin carcinogenesis. The keratin 1 promoter was used to generate HK1.ras and HK1.bcl-2 transgenic mice, which were subsequently crossed to generate HK1.ras/bcl-2 double transgenic mice. The apoptotic index (AI) following UV-irradiation was significantly lower in HK1.bcl-2 and HKI.ras/bcl-2 epidermis compared to control littermates. Interestingly, the AI of HK1.ras/bcl-2 mice was significantly lower than even HK1.bcl-2 mice following UV-irradiation. To investigate the interaction of these oncogenes in skin tumorigenesis, a two-stage chemical carcinogenesis protocol was used to induce tumors. The individual contributions of Ha-ras and bcl-2 to papilloma latency, incidence, and growth rate in HK1.ras/bcl-2 double transgenic mice was marginally additive. Papillomas arising in HK1.ras transgenic mice exhibited the highest rate of apoptosis whereas papillomas arising in the HK1.ras/bcl-2 double transgenic mice exhibited rates of apoptosis that were significantly lower than papillomas arising in either control littermate or HK1.ras mice. Constitutive expression of either Ha-ras or bcl-2 exhibited similar rates of malignant tumor progression and they were not significantly different than control littermates. Importantly, when these two oncoproteins were coexpressed, a significant, and synergistic, increase in malignant transformation was observed.
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PMID:Cooperation of Ha-ras and Bcl-2 during multistep skin carcinogenesis. 1753 44