Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skin tumour development was studied in groups of mice painted once with 125 mug of 3-methylcholanthrene (MCA) either at 12:00 or at 24:00 MET. Eight animals were kept in each box. The animals were observed weekly for 20 months and all tumours were registered. There was no difference between the two groups of mice as regards tumour induction time or number of papilloma-bearing mice. In the groups of mice treated at 24:00 the number of skin tumours to develop was 9 per cent higher than in groups of mice treated at 12:00. This difference in papilloma yields is not statistically significant. Among female mice painted at 24:00 carcinoma-bearing animals were significantly more numerous (50 per cent) than among those painted at 12:00, whereas there was no difference between the groups of male mice. Considering the groups collectively (males + females), the intergroup difference (17 per cent) in advantage of painting at 24:00 was barely significant (0.5 less than p less than 0.10). There was no difference between the groups as regards the total number of carcinomas to occur. When the tumour yields in individual boxes were found to vary greatly. The slight increase in tumour yield after night painting correlates with the circadian variation in proliferative activity of the epidermidis. Previous reports in the literature have shown similar differences. Further investigations and better methods seem necessary before a definite conclusion can be drawn concerning a possible diurnal variation in the susceptibility of mouse skin to chemical carcinogenesis. It is also emphasized that it is necessary to exercise great caution when the results of classical epidermal chemical carcinogenesis experiments are to be interpreted. It seems necessary to observe animals for at least 15 months before any conclusion can be drawn.
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PMID:Is there a diurnal variation in the susceptibility of mouse skin to the tumorigenic action of methylcholanthrene? A study of tumour yield with special reference to the variation between cages. 98 89

To investigate the function of c-Jun during skin development and skin tumor formation, we conditionally inactivated c-jun in the epidermis. Mice lacking c-jun in keratinocytes (c-jun(Deltaep)) develop normal skin but express reduced levels of EGFR in the eyelids, leading to open eyes at birth, as observed in EGFR null mice. Primary keratinocytes from c-jun(Deltaep) mice proliferate poorly, show increased differentiation, and form prominent cortical actin bundles, most likely because of decreased expression of EGFR and its ligand HB-EGF. In the absence of c-Jun, tumor-prone K5-SOS-F transgenic mice develop smaller papillomas, with reduced expression of EGFR in basal keratinocytes. Thus, using three experimental systems, we show that EGFR and HB-EGF are regulated by c-Jun, which controls eyelid development, keratinocyte proliferation, and skin tumor formation.
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PMID:c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. 1279 Dec 72

A transgenic mouse line overexpressing a constitutively active mutant of MEK1, a downstream effector of Ras, driven by the keratin 14 (K14) promoter, has been used to test the hypothesis that ornithine decarboxylase (ODC) induction during tumor promotion following a single initiating event [i.e., the activation of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway], is a necessary step in skin carcinogenesis. K14-MEK mice exhibit moderate hyperplasia, with spontaneous skin tumor development within 5 weeks of birth. Analysis of epidermis and dermis showed induction of MEK protein and ERK1/ERK2 phosphorylation, but no change in Akt-1, suggesting that the PI 3-kinase pathway, another pathway downstream of ras, is not activated. Examination of tumors revealed high levels of ODC protein and activity, indicating that activation of signaling cascades dependent on MEK activity is a sufficient stimulus for ODC induction. When K14-MEK mice were given alpha-difluoromethylornithine (DFMO), a suicide inactivator of ODC, in the drinking water from birth, there was a dramatic delay in the onset of tumor growth ( approximately 6 weeks), and only 25% of DFMO-treated mice developed tumors by 15 weeks of age. All untreated K14-MEK mice developed tumors by 6 weeks of age. Treatment of tumor-bearing mice with DFMO reduced both tumor size and tumor number within several weeks. Tumor regression was the result of both inhibition of proliferation and increased apoptosis in tumors. The results establish ODC activation as an important component of the Raf/MEK/ERK pathway, and identify K14-MEK mice as a valuable model with which to study the regulation of ODC in ras carcinogenesis.
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PMID:Induction of ornithine decarboxylase activity is a necessary step for mitogen-activated protein kinase kinase-induced skin tumorigenesis. 1569 1

Specific germline activating point mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) result in autosomal dominant human skeletal dysplasias. The identification in multiple myeloma and in two epithelial cancers-bladder and cervical carcinomas-of somatic FGFR3 mutations identical to the germinal activating mutations found in skeletal dysplasias, together with functional studies, have suggested an oncogenic role for this receptor. Although acanthosis nigricans, a benign skin tumor, has been found in some syndromes associated with germinal activating mutations of FGFR3, the role of activated FGFR3 in the epidermis has never been investigated. Here, we targeted an activated receptor mutant (S249C FGFR3) to the basal cells of the epidermis of transgenic mice. Mice expressing the transgene developed benign epidermal tumors with no sign of malignancy. These skin lesions had features in common with acanthosis nigricans and other benign human skin tumors, including seborrheic keratosis, one of the most common benign epidermal tumors in humans. We therefore screened a series of 62 cases of seborrheic keratosis for FGFR3 mutations. A large proportion of these tumors (39%) harbored somatic activating FGFR3 mutations, identical to those associated with skeletal dysplasia syndromes and bladder and cervical neoplasms. Our findings directly implicate FGFR3 activation as a major cause of benign epidermal tumors in humans.
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PMID:Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. 1577 91

ped/pea-15 is a cytosolic protein performing a broad antiapoptotic function. We show that, upon DMBA/TPA-induced skin carcinogenesis, transgenic mice overexpressing ped/pea-15 (Tg(ped/pea-15)) display early development of papillomas and a four-fold increase in papilloma number compared to the nontransgenic littermates (P<0.001). The malignant conversion frequency was 24% for the Tg(ped/pea-15) mice and only 5% in controls (P<0.01). The isolated application of TPA, but not that of DMBA, was sufficient to reversibly upregulate ped/pea-15 in both untransformed skin and cultured keratinocytes. ped/pea-15 protein levels were also increased in DMBA/TPA-induced papillomas of both Tg(ped/pea-15) and control mice. Isolated TPA applications induced Caspase-3 activation and apoptosis in nontransformed mouse epidermal tissues. The induction of both Caspase-3 and apoptosis by TPA were four-fold inhibited in the skin of the Tg(ped/pea-15) compared to the nontransgenic mice, accompanied by a similarly sized reduction in TPA-induced JNK and p38 stimulation and by constitutive induction of cytoplasmic ERK activity in the transgenics. ped/pea-15 expression was stably increased in cell lines from DMBA/TPA-induced skin papillomas and carcinomas, paralleled by protection from TPA apoptosis. In the A5 spindle carcinoma cell line, antisense inhibition of ped/pea-15 expression simultaneously rescued sensitivity to TPA-induced Caspase-3 function and apoptosis. The antisense also reduced A5 cell ability to grow in semisolid media by 65% (P<0.001) and increased by three-fold tumor latency time (P<0.01). Thus, the expression levels of ped/pea-15 control Caspase-3 function and epidermal cell apoptosis in vivo and determine susceptibility to skin tumor development.
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PMID:Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. 1604 59

Keloids are abnormal fibrous growths of the dermis that develop only in response to wounding and represent a form of benign skin tumor. Previous studies have shown increased protein levels of TGF-beta in keloid tissue, suggesting a strong association with keloid formation leading us to examine mechanisms for why it is more highly expressed in keloids. Here, we use serum stimulation as an in vitro model to mimic a component of the wound microenvironment and examine differential gene expression in keloid human fibroblasts (KFs) vs. normal human fibroblasts (NFs). Transcription of TGF-beta2 was rapid and peaked between 1 and 6 h after serum stimulation in KFs vs. NFs. We confirmed increased TGF-beta activity in the conditioned medium from KFs, but not NFs. Inhibition of second messenger signaling pathways demonstrated that only the p38 MAPK inhibitor SB-203580 could block upregulation of TGF-beta2 following serum stimulation in KFs. Immunoblotting demonstrated that p38 MAPK was phosphorylated within 15 min and was maintained at a high level in KFs but not in NFs. The transcription factors activating transcription factor-2 and Elk-1 are activated by p38 MAPK, and also showed rapid and prolonged phosphorylation kinetics in KFs but not in NFs. In conclusion, increased TGF-beta2 transcription in response to serum stimulation in KFs appears to be mediated by the p38 MAPK pathway. This suggests the mechanism of keloid pathogenesis may be due in part to an inherent difference in how the fibroblasts respond to wounding.
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PMID:P38 MAP kinase mediates transforming growth factor-beta2 transcription in human keloid fibroblasts. 1646 96

We previously showed that rasH2 transgenic mice carrying the human c-Ha-ras protooncogene are highly susceptible to chemical skin carcinogenesis. In the dermis of rasH2 mice, mast cells are recruited constitutively, and the number of mast cells increases more than in wild-type mice in response to treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. To determine whether enhanced skin tumor development in rasH2 mice is dependent on the recruitment of mast cells, we generated rasH2 KIT(W/Wv) mice by crossing rasH2 mice and W or W(v) KIT mutants, and examined the chemical skin carcinogenesis. In rasH2 KIT(W/Wv) mice, mast cells were not found in the dermis either before or after treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Papilloma multiplicity was up to 4.6-fold higher in rasH2 KIT(+/+) mice compared with their rasH2 KIT(W/Wv) siblings. At 12 weeks after the experiment began, the volumes of tumors were significantly smaller in rasH2 KIT(W/Wv) relative to rasH2 KIT(+/+) mice (rasH2 KIT(W/Wv): 29.2 +/- 19.9 mm(3) versus rasH2 KIT(+/+): 179.6 +/- 726.6 mm(3); P = 0.0153). There was no difference in the latency or multiplicity of papillomas between mice without the rasH2 transgene, KIT(W/Wv) mice and their wild-type littermates. Western blot analysis showed that expression of H-RAS protein in the skin was equivalent in rasH2 KIT(W/Wv) and rasH2 KIT(+/+) mice. In conclusion, the inhibition of c-kit decreased H-ras-induced skin carcinogenesis. The suppression of c-kit may be a unique and effective target as a preclinical model of cancer treatment where the activation of H-ras has a significant role. Targeting mast cells could also be a potential strategy for treating malignancies.
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PMID:Decreased c-kit function inhibits enhanced skin carcinogenesis in c-Ha-ras protooncogene transgenic mice. 1768 12

We report a case of advanced breast cancer (T4b, N3c, M1) achieving a significant improvement on QOL by multi-disciplinary therapy and S-1 administration. The patient was a 59-year-old woman who had ulcerative breast lump with bleeding. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma negative for estrogen receptor, progesterone receptor, and HER2/neu protein expression. The aspiration biopsy cytology was performed from skin lesion, the diagnosis was class V. She received 6 cycles of tri-weekly CEF (C: 500 mg, E: 60 mg, F: 500 mg/m2) therapy. The effect of the breast tumor was partial response, and the bleeding from the breast lump was improved. But the response from metastatic skin tumor was less satisfactory. We performed a radiation therapy (20 Gy) to metastatic skin tumor, and the lesion disappeared after the radiation therapy. Then, we tried docetaxel, but the side effect appeared. So, we started administering S-1 after docetaxel. One year later, she was estimated to be in the long stable disease. Multi-disciplinary therapy can improve a patient QOL and the clinical outcomes in Stage IV advanced breast cancer.
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PMID:[A case of advanced breast cancer successfully treated with multi-disciplinary therapy and S-1 administration]. 1821

In the present study, the chemopreventive effect of topical application of perillyl alcohol (POH) on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis and its possible mechanisms of action in Swiss albino mice were investigated. We evaluated the effect of pretreatment of POH (6 and 12 mg/kg body weight) on TPA (2 microg/200 microl of acetone)-induced skin edema, hyperplasia, peroxidase damage and modulation in activities of catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione contents. Application of POH 30 min prior to TPA treatment, showed a protective effect in almost all the investigated parameters. Additionally, pretreatment with POH showed a significant inhibition of ornithine decarboxylase (ODC) activity and [(3)H] thymidine incorporation into epidermal DNA. In promotion phase, a significant reduction was found in tumor incidence and tumor burden in mice pretreated with POH (12 mg/kg body weight) with extension of the latency period from 4 to 8 weeks as compared to those treated with TPA alone. POH significantly suppressed the Ras/Raf/ERK pathway and induced apoptosis in Swiss albino mice skin. Our findings suggested that the chemopreventive efficacy of POH is probably due to the inhibition of oxidative stress responses, inhibition of the Ras cell proliferation pathway and induction of apoptosis in murine skin tumor promotion phase.
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PMID:Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis. 1916 93

Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus,we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype.
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PMID:A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. 1972 38


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