Abnormalities of epidermal differentiation associated with expression of the human papillomavirus type 1 early region in transgenic mice

Tinsley, Jonathon M.; Fisher, Cindy L.; Searle, Peter F.

doi:10.1099/0022-1317-73-5-1251

Cited by 23 publications

(15 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The tissue distribution oftransgene expression was therefore broadly as expected, though expression in the reproductive tract appeared relatively low and expression in the glandular stomach was not anticipated. It is interesting that expression of the HPV-1 early region from the same promoter in a single line of transgenic mice was biased towards expression in cutaneous epithelia (Tinsley et al, 1992) whereas the pattern of expression of the HPV-16 transgene in all of the lines described here was considerably higher in mucosal epithelia, suggesting that viral sequences within the constructs might contribute to the tissue specificity of expression.…”

Section: Expression Of Hpv-16 Mrnas In Tissues and Tumoursmentioning

confidence: 92%

Stomach Cancer in Transgenic Mice Expressing Human Papillomavirus Type 16 Early Region Genes From a Keratin Promoter

Searle

Thomas

Faulkner

et al. 1994

Journal of General Virology

Self Cite

View full text Add to dashboard Cite

Certain human papillomaviruses (HPVs) have been implicated as important contributory factors in the development of cervical carcinoma and other epithelial malignancies. In order to investigate the role of papillomavirus early gene expression in epithelial oncogenesis in vivo, we produced transgenic mice expressing HPV-16 early region genes from the promoter of the bovine keratin 6 gene. Spliced transcripts were detected in the tongue, forestomach, glandular stomach, female reproductive tract and tail skin of these mice. This expression was initially asymptomatic. However, at increasing frequency after approx. 100 days, solitary glands within the gastric mucosa became colonized with small dysplastic ceils. Later this abnormal cell population spread within the glandular mucosa, invaded the submucosa and outer muscular wall of the stomach, and commonly metastasized to local lymph nodes and the liver. The appearance and staining characteristics of the tumours suggested their classification as malignant carcinoids, originating from the neuroendocrine enterochromaffin-like cells. Expression of HPV mRNAs was increased in the tumours, though it remained comparable to that in forestomach and tongue. The mean age at tumour presentation was 246 days in males and 352 days in females, all transgenic mice in eight independent lines were similarly susceptible. This study confirms the oncogenicity of HPV-16 early region genes, and establishes a model system in which to investigate mechanisms of malignant progression and possible therapeutic strategies for HPV-associated tumours.

show abstract

Section: Expression Of Hpv-16 Mrnas In Tissues and Tumoursmentioning

confidence: 92%

Stomach Cancer in Transgenic Mice Expressing Human Papillomavirus Type 16 Early Region Genes From a Keratin Promoter

Searle

Thomas

Faulkner

et al. 1994

Journal of General Virology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The early genome region of HPV1, which induces benign plantar warts, has been expressed under control of the keratin-6 promoter in CBA/C57B1-transgenic mice but this only led to a transient hyperproliferation (35). Transgenic IRCxFVB mice with keratin-1 promoter-driven E6/E7 genes of the cervical cancer associated HPV18 developed papillomas that remained benign for up to 12 months (36).…”

Section: Resultsmentioning

confidence: 99%

Development of Skin Tumors in Mice Transgenic for Early Genes of Human Papillomavirus Type 8

et al. 2005

View full text Add to dashboard Cite

The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo. (Cancer Res 2005; 65(4): 1394-400)

show abstract

“…have taken advantage of the epithelial specificity and strength of cytokeratin promoters (Bailleul et al 1990;Vassar and Fuchs 1991;Sch6nrich et al 1992;Tinsley et al 1992;Turksen et al 1992). Two features of these cytokeratin promoters may affect their general application for targeting transgene expression to the epidermis.…”

Section: Use Of Cytokeratin Promoters For Targeting Transgenes To Thementioning

confidence: 99%

“…Second, the promoters of cytokeratin genes 10 and 14 are constitutively active in the epidermis as soon as this organ develops during embryogenesis (Dale et al 1985}, which may in some cases result in premature death of transgenic animals or disturb experiments focusing on adult epidermis. Short regions (<2.2 kb) of the promoter region of cytokeratin IV* have been used so far to direct transgene expression to a subpopulation of medullary epithelial cells in the thymus (Sch6nrich et al 1992} and to the skin of paws and tails (Tinsley et al 1992}. In the latter case, transgene expression was found in only 20% of the transgenic founder animals and was generally very weak (Tinsley et al 1992), indicating a strong dependency of these short promoter fragments on the site of integration.…”

Section: Genes and Development 209mentioning

confidence: 99%

Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles.

Blessing¹,

Nanney²,

King³

et al. 1993

Genes Dev.

156

101

View full text Add to dashboard Cite

There is increasing evidence that members of the TGF-13 superfamily are important regulators of epithelial growth and differentiation in vivo. Here, transgenic mice have been used to study the role of the TGF-{3-related growth [actors BMP-2 and BMP-4 in hair and whisker development. In the mature hair follicle, BMP-2 transcripts are normally seen only in precortex cells at the base of the hair shaft. In the transgenic mice reported here, BMP-4, a closely related molecule, has been ectopically expressed in the outer root sheath of hair and whisker follicles using an expression vector based on the bovine cytokeratin IV* promoter. In response to transgene expression, both outer root sheath cells below the stem cell compartment and hair matrix cells around the dermal papilla cease proliferation. In addition, the expression pattern of cytokeratin markers is disturbed in some transgenic hair follicles. These results support a model in which members of the TGF-13 superfamily play an active role in the inhibition of cell proliferation and the onset of expression of trichocyte-specific genes that take place when cells leave the matrix of the follicle and differentiate into shaft cells.

show abstract

Abnormalities of epidermal differentiation associated with expression of the human papillomavirus type 1 early region in transgenic mice

Cited by 23 publications

References 24 publications

Stomach Cancer in Transgenic Mice Expressing Human Papillomavirus Type 16 Early Region Genes From a Keratin Promoter

Stomach Cancer in Transgenic Mice Expressing Human Papillomavirus Type 16 Early Region Genes From a Keratin Promoter

Development of Skin Tumors in Mice Transgenic for Early Genes of Human Papillomavirus Type 8

Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles.

Contact Info

Product

Resources

About