scholarly journals Cell Type-Specific p38δ Targeting Reveals a Context-, Stage-, and Sex-Dependent Regulation of Skin Carcinogenesis

2019 ◽  
Vol 20 (7) ◽  
pp. 1532 ◽  
Author(s):  
Alexi Kiss ◽  
Aaron Koppel ◽  
Emily Murphy ◽  
Maxwell Sall ◽  
Meral Barlas ◽  
...  

Activation and/or upregulated expression of p38δ are demonstrated in human skin malignancies including cutaneous squamous cell carcinoma, suggesting a role for p38δ in skin carcinogenesis. We previously reported that mice with germline deletion of the p38δ gene are significantly protected from chemical skin carcinogenesis. Here, we investigated the effects of cell-selective targeted ablation of p38δ in keratinocytes and in immune (myeloid) cells on skin tumor development in a two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical mouse skin carcinogenesis model. Conditional keratinocyte-specific p38δ ablation (p38δ-cKO∆K) did not influence the latency, incidence, or multiplicity of chemically-induced skin tumors, but led to increased tumor volume in females during the TPA promotion stage, and reduced malignant progression in males and females relative to their wild-type counterparts. In contrast, conditional myeloid cell-specific p38δ deletion (p38δ-cKO∆M) inhibited DMBA/TPA-induced skin tumorigenesis in male but not female mice. Thus, tumor onset was delayed, and tumor incidence, multiplicity, and volume were reduced in p38δ-cKO∆M males compared with control wild-type males. Moreover, the percentage of male mice with malignant tumors was decreased in the p38δ-cKO∆M group relative to their wild-type counterparts. Collectively, these results reveal that cell-specific p38δ targeting modifies susceptibility to chemical skin carcinogenesis in a context-, stage-, and sex-specific manner.

1995 ◽  
Vol 14 (2) ◽  
pp. 118-129 ◽  
Author(s):  
Peter Krieg ◽  
Andreas Kinzig ◽  
Marion Ress-Löschke ◽  
Sonja Vogel ◽  
Ben Vanlandingham ◽  
...  

Genome ◽  
2004 ◽  
Vol 47 (5) ◽  
pp. 931-946 ◽  
Author(s):  
Ssucheng J Hsu ◽  
Hiroki Nagase ◽  
Allan Balmain

Studies of mouse models for multistage carcinogenesis have led to the identification of a susceptibility locus for skin tumor development (Skts9) in the proximal region of mouse chromosome 16. This chromosome region shows a loss of heterozygosity or an allelic imbalance in mouse skin and pancreatic islet carcinoma, and has been associated with angiogenesis. The microsatellite marker D16Mit2, which has the strongest linkage to skin tumor susceptibility, was used to screen a bacterial artificial chromosome (BAC) library, leading to the identification of the histidine-rich glycoprotein (Hrg) and Fetuin-B as the most tightly linked genes. These genes are members of a cystatin-like superfamily that includes the neighboring genes Kng and Ahsg/Fetuin. Overexpression of Fetuin-B in skin squamous carcinoma cells led to suppression of tumor growth in nude mice. The neighboring genes Kng and Ahsg also have potential roles in angiogenesis and (or) tumor development, and several genes in this locus may be candidates for the Skts9 gene.Key words: Skts9, Hrg, Fetuin-B, cystatin-like superfamily.


2021 ◽  
Author(s):  
Christine Hoesl ◽  
Thomas Fröhlich ◽  
Christian Posch ◽  
Hermann Kneitz ◽  
Matthias Goebeler ◽  
...  

2005 ◽  
Vol 102 (26) ◽  
pp. 9253-9257 ◽  
Author(s):  
H. Nishikawa ◽  
T. Kato ◽  
I. Tawara ◽  
T. Takemitsu ◽  
K. Saito ◽  
...  

2005 ◽  
Vol 25 (1) ◽  
pp. 88-99 ◽  
Author(s):  
Adrien Kissenpfennig ◽  
Smina Aït-Yahia ◽  
Valérie Clair-Moninot ◽  
Hella Stössel ◽  
Edgar Badell ◽  
...  

ABSTRACT Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin − / − mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin − / − mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin − / − LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin − / − mice were not impaired in their capacity to process native OVA protein for I-A b -restricted presentation to CD4+ T lymphocytes or for H-2K b -restricted cross-presentation to CD8+ T lymphocytes. langerin − / − mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin − / − and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin − / − C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG.


2021 ◽  
Vol 22 (13) ◽  
pp. 6736
Author(s):  
Josefa P. Alameda ◽  
Verónica A. García-García ◽  
Silvia López ◽  
Ana Hernando ◽  
Angustias Page ◽  
...  

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.


Cell Cycle ◽  
2012 ◽  
Vol 11 (2) ◽  
pp. 335-342 ◽  
Author(s):  
Xian Wang ◽  
Christopher Sistrunk ◽  
Paula L. Miliani de Marval ◽  
Yongbaek Kim ◽  
Marcelo L. Rodriguez-Puebla

1997 ◽  
Vol 114 (1-2) ◽  
pp. 183-184 ◽  
Author(s):  
Kwang-Kyun Park ◽  
Young-Joon Surh

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