Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter

Bailleul, Bernard; Surani, M. Azim; White, Stephen; Barton, Sheila C.; Brown, Ken; Blessing, Manfred; Jorcano, J.J.; Balmain, Allan

doi:10.1016/0092-8674(90)90115-u

Cited by 243 publications

(164 citation statements)

References 52 publications

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“…In the mouse skin carcinogenesis model over 90% of papillomas and carcinomas initiated by DMBA have a speci®c A?T transversion in the codon 61 of the Harvey-ras gene (Balmain et al, 1984;. This mutation is su cient to initiate skin in vivo, but secondary events are necessary to induce the development of tumors Bailleul et al, 1990). Our transgenic mice showed an increased malignant conversion frequency after initiation with DMBA without an ongoing exogeneous tumor promotion.…”

Section: Discussionmentioning

confidence: 71%

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

et al. 1998

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The role of Transforming growth factor beta (TGF-b) in carcinogenesis is complex. There are reports on both tumor inhibition and tumor promotion by TGF-b. To elucidate the complex role of TGF-b in epithelial carcinogenesis, we generated transgenic mice overexpressing a dominant negative type II TGF-b receptor in the basal cell compartment and in follicular cells of the skin. Despite the reduced responsiveness of transgenic keratinocytes to TGF-b, both proliferation and di erentiation were normal in non-irritated epidermis of these transgenic mice. Thus, interruption of signaling of all three isoforms of TGF-b in basal and follicular cells does not disturb tissue homeostasis. However, during tumor promotion transgenic mice showed an elevated level of proliferation in the epidermis. This hyperproliferation correlated with a very early onset of carcinoma development and a malignant conversion frequency of 30% from benign papillomas to carcinomas. By comparison, the conversion frequency in wild-type mice of this strain has previously been reported as 5.5%. Even without induction of hyperproliferation by tumor promoters, transgenic mice developed far more carcinomas as controls when treated with a carcinogen. This result indicates that there is a synergistic e ect between loss of TGF-b responsiveness and mutations caused by initiation with a carcinogen leading to an endogeneous tumor promotion in initiated cells only.

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Section: Discussionmentioning

confidence: 71%

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

et al. 1998

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“…The Keratin 10 reporter (K10-Luc) contains 1665 bp of 5' anking and untranslated sequence from the human cytokeratin 10 gene linked to ®re¯y luciferase (Rieger and Franke, 1988;Andersen et al, 1993). The cytokeratin 10 promoter has been previously used to express transgenes in a di erentiation-speci®c manner in mice (Bailleul et al, 1990;Blessing et al, 1996). The b actin-CAT reporter gene (Saunders et al, 1993a) or b actin-Luciferase reporter gene were used to normalize for transfection e ciency.…”

Section: Transfection Of Cells and Reporter Assaysmentioning

confidence: 99%

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

et al. 2000

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Squamous di erentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis. To explore the relationship between E2F-1 and squamous di erentiation further, we examined the e ect of altering E2F activity in primary human keratinocytes induced to di erentiate. Promoter activity for the proliferationassociated genes, cdc2 and keratin 14, are inhibited during squamous di erentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes. Overexpression of E2F-1 also suppressed the expression of di erentiation markers (transglutaminase type 1 and keratin 10) in di erentiated keratinocytes. Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce di erentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-speci®c marker genes and suppresses squamous di erentiation-speci®c marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas.

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“…The immunoblotting was carried out using pan-ras (Val 12 ) (Oncogene Research Products), a monoclonal antibody raised against a Val 12 peptide. This antibody reacts specifically with Val 12 Ha-ras but not Gly 12 or Asp 12 ras p21 protein. 35 The blot was blocked with 1% Tween 20 and 5% nonfat dry milk, and then visualized using the enhanced chemilumine-scence (ECL) system with horseradish peroxidase-conjugated goat anti-mouse IgG antibody (Amersham).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…This contrasts with the effects seen in previous studies of targeted Ha-ras expression to other epidermal cells in which malignant conversion is rarely observed. 12,14,15 The relationship between keratoacanthoma and squamous cell carcinoma (SCC) has been debated for several decades. 21 Because of its rapid growth, occasional metastasis, and high histological similarity to SCC, keratoacanthoma has been suggested to be a type of SCC.…”

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confidence: 99%

“…The roles of activated Ha-ras in skin tumor development are further supported by animal studies, including carcinogen-treated animals [7][8][9][10][11] and transgenic animals. [12][13][14][15][16][17] Mouse skin carcinogenesis as a biological model has been used to study Ha-ras activation-related skin tumors for many years. The Sencar mice are the most widely used model for studying so-called two-stage carcinogenesis because of their sensitivity to the carcinogens 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA).…”

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confidence: 99%

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Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

Peng

Griffith

Han

et al. 1999

The American Journal of Pathology

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Activated ras genes have been frequently identified in both benign and malignant human tumors , including keratoacanthoma and squamous cell carcinoma. In this study , we developed two lines of transgenic rabbits in which the expression of EJras has been specifically targeted to the rabbit epidermal keratinocytes , using the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1 transgenic progenies developed multiple keratoacanthomas at about 3 days after birth. The rabbits developed an average of 20 tumors , which usually reached the size of approximately 1 cm in diameter and then spontaneously regressed in about 2 months , similar to keratoacanthoma regression in humans. In addition , up to 18% of the rabbits then developed squamous cell carcinoma at about 5 months of age. The expression of EJras was detectable in all of the keratoacanthomas and squamous cell carcinomas. These results strongly support the involvement of the ras oncogene in both the initiation and regression of keratoacanthoma , and in the development of squamous cell carcinomas. These novel transgenic rabbits , with their consistent tumorigenic phenotype at an early age , high similarity to the human lesions, and easy accessibility for examination , manipulation, biopsy , and treatment , should provide a unique model system for studying ras activation-related tumor initiation , regression , and progression , and for evaluating antitumor therapies. (Am J Pathol 1999, 155:315-324)Ras genes encode a family of plasma membrane-bound proteins (p21ras) that function as intermediates in cell signal transduction pathways. These proteins play a pivotal role in regulating cell growth and differentiation in nearly all studied eukaryotic cell types. 1 The activity of ras proteins as regulating switches is strictly controlled by cycling between active GTP-bound and inactive GDPbound states. 2 The active and inactive cycling of the p21ras proteins may be broken because of a point mutation at position 12, 13, or 61 of the proteins, which has been found in both experimental and spontaneous tumors. This cellular transformation property is considered to be due to the extended life and resultant accumulation of p21ras proteins in the active GTP state, 3 which leads to tumorigenesis due to loss of regulatory control of cell proliferation and differentiation. However, many aspects of ras mutation-related neoplasia still remain to be elucidated, especially the dual roles of activated ras genes in cell growth stimulation or differentiation, and its correlation with tumor initiation, regression, and progression.It is well known that carcinogenesis is a complex multistep process that usually involves mutation and/or inappropriate expression of certain cellular genes, such as the mutational activation of proto-oncogenes and the inactivation of tumor suppressor genes. Among the oncogenes, activated ras genes have been found in a wide variety of human tumors, and ranges from 10 -20% Haras activation in bladder carcinomas to 85-100% Ki-ras in colorec...

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Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter

Cited by 243 publications

References 52 publications

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

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