Increased expression of p50-NF-κB and constitutive activation of NF-κB transcription factors during mouse skin carcinogenesis

Budunova, Irina; Pérez, Paloma; Vaden, Valerie R.; Spiegelman, Vladimir S.; Slaga, Thomas J.; Jorcano, José L.

doi:10.1038/sj.onc.1203104

Cited by 114 publications

(100 citation statements)

References 48 publications

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“…This could also explain the increased proliferation and enhanced aggressiveness of C57-CYLD C/S cells, as activated nuclear Bcl3/p50/p52 expression has been shown to promote cell proliferation and oncogenesis through the activation of the cyclin D1 gene in breast and nasopharyngeal human tumors (Cogswell et al, 2000;Thornburg et al, 2003). Increased nuclear localization of p50/p52 and Bcl3 was also found in advanced stages of mouse skin carcinomas (Budunova et al, 1999). Nuclear Bcl3 has been detected in cylindroma cells, whereas normal skin keratinocytes retain Bcl3 in the cytoplasm (Massoumi et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD C/S ) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD C/S mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD C/S transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD C/S exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD C/S tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

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Section: Discussionmentioning

confidence: 95%

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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“…21 BCL-3 also can bind to the promoter of cyclin D1, enhancing progression of the cell cycle from G1 to S phase. 4,22 Several studies have shown that BCL-3 is activated and may play a role in human breast cancer, 23 mouse skin carcinogenesis, 24 and hepatocyte proliferation, 25 which suggest that BCL-3 is involved in carcinogenesis and cell growth. Additionally, it was reported that BCL-3 affects retinoid X receptor functions in some tissues, and that retinoid X receptor plays a role in the potential tumorigenesis mediated by BCL-3.…”

Section: Bcl-3 In Lymphomasmentioning

confidence: 99%

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases

et al. 2004

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The bcl-3 gene at chromosome 19q13 encodes a member of the IjB family involved in regulating the NFjB pathway. Originally identified by its involvement in the rare t(14:19)(q32;q13), BCL-3 expression has never been analyzed in a wide variety of lymphomas. We assessed BCL-3 expression in 353 cases of non-Hodgkin lymphoma and Hodgkin lymphoma using formalin-fixed, paraffin-embedded tissue specimens, a monoclonal antibody specific for BCL-3, and immunohistochemical methods. Of 172 B-cell lymphomas, 10 (6%) were positive for BCL-3, including six of 23 (26%) diffuse large B-cell lymphoma, one of 17 (6%) small lymphocytic lymphoma, one of 26 (4%) follicular lymphoma, and two of 49 (4%) mantle cell lymphoma. All other B-cell neoplasms were negative, including marginal zone lymphoma (n ¼ 24, 11 extranodal, nine nodal, four splenic), Burkitt lymphoma (n ¼ 10), lymphoplasmacytic lymphoma (n ¼ 10), lymphoblastic lymphoma (n ¼ 8), and plasmacytoma (n ¼ 5). Of 111 T/NK-cell lymphomas, 25 (23%) were positive for BCL-3, including 13 of 40 (32%) anaplastic large-cell lymphoma, three of 10 (30%) angioimmunoblastic T-cell lymphoma, two of eight (25%) extranodal NK/T-cell lymphoma of nasal type, three of 12 (25%) mycosis fungoides, one of five (20%) enteropathy-type T-cell lymphoma, and two of 21 (10%) peripheral T-cell lymphoma unspecified. All other T-cell neoplasms were negative, including lymphoblastic lymphoma (n ¼ 6), prolymphocytic leukemia (n ¼ 6), and subcutaneous panniculitis-like T-cell lymphoma (n ¼ 3). Of 70 Hodgkin lymphomas, of all types, 29 (41%) were positive for BCL-3. The relatively high frequency of BCL-3 expression in some non-Hodgkin and Hodgkin lymphoma types raises the possibility that BCL-3 is involved in the pathogenesis of these tumors, and may be a target of new therapies.

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“…Our earlier work revealed that GR overexpression dramatically reduced NF-kB binding activity and expression of kB-responsive genes in skin of K5-GR transgenic mice (Perez et al, 2001). We also showed that NF-kB is constitutively activated in mouse skin tumors induced by the DMBA/TPA protocol, partially because of a strong increase in p50 (NF-kB1) expression and a decrease in the steady-state level of IkBa inhibitor in comparison with untreated epidermis (Budunova et al, 1999). Therefore, we evaluated the NF-kB status in K5-GR/ras+ and w.t./ras+ tumors.…”

Section: Effect Of Gr Overexpression On Nf-kbmentioning

confidence: 99%

“…Whole-cell protein extracts were prepared as previously described (Budunova et al, 1999), separated by SDS-PAGE and transferred to Immobilon-P membrane (Millipore Corporation, Bedford, MA, USA). Membranes were stained with Ponceau S to verify equal protein loading and transfer.…”

Section: Western Blottingmentioning

confidence: 99%

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

et al. 2003

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y These authors contributed equally to the work 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-jB) transcription factor had resulted in NF-jB blockage in K5-GR/ras+ tumors. We discuss the role of NF-jB blockage in tumor-suppressor effect of GR.

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Increased expression of p50-NF-κB and constitutive activation of NF-κB transcription factors during mouse skin carcinogenesis

Cited by 114 publications

References 48 publications

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

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