Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis.
Glucocorticoids are effective inhibitors of epidermal proliferation and skin tumorigenesis. Glucocorticoids affect cellular functions via glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated skin-targeted transgenic mice overexpressing GR under control of the keratin5 promoter (K5-GR mice). To test the hypothesis that GR plays a role as a tumor suppressor in skin, we bred K5-GR transgenic mice with Tg.AC transgenic mice, which express v-Ha-ras oncogene in the skin, and compared the susceptibility of F1 offspring to TPA-induced skin carcinogenesis. GR overexpression in the epidermis dramatically inhibited skin tumor development. In K5-GR/ras+ double transgenic mice papillomas developed later and the average number of tumors per animal was 15% (in males) and 40% (in females) of the number seen in wild type (w.t./ras+) littermates. In addition, the papillomas in w.t./ras+ animals were eight to nine times larger. GR overexpression resulted in a decrease in keratinocyte proliferation combined with a modest increase in apoptosis and differentiation of keratinocytes in K5-GR/ras+ papillomas. Our data clearly indicate that interference of GR transgenic protein with nuclear factor kappa B (NF-kappaB) transcription factor had resulted in NF-kappaB blockage in K5-GR/ras+ tumors. We discuss the role of NF-kappaB blockage in tumor-suppressor effect of GR.
Budunova
Irina V
IV
AMC Cancer Research Center, 1600 Pierce Street, Denver, CO 80214, USA.
Kowalczyk
Dariusz
D
Pérez
Paloma
P
Yao
Ya Juan
YJ
Jorcano
José L
JL
Slaga
Thomas J
TJ
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D004817:Epidermis / Q000378:metabolism; D005260:Female; D053569:Keratin-15; D053555:Keratin-5; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010212:Papilloma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D025521:Tumor Suppressor Proteins; D007633:Keratins; D015689:Oncogene Protein p21(ras)