Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 185, Issue 9, Pages 2354-2363Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.05.018
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Funding
- Cancer Research UK programme [A13044]
- British Skin Foundation [4054]
- European Research Council [250170]
- Wellcome Trust [098439/Z/12/2]
- European Research Council (ERC) [250170] Funding Source: European Research Council (ERC)
- Cancer Research UK [13044] Funding Source: researchfish
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NF-kappa B signaling plays a crucial role in regulating proliferation and differentiation in the epidermis. Alterations in the NF-kappa B pathway can lead to skin pathologies with a significant burden to human health such as psoriasis and cutaneous squamous cell carcinoma (cSCC). Caspase recruitment domain (CARD)-containing scaffold proteins are key regulators of NF-kappa B signaling by providing a Link between membrane receptors and NF-kappa B transcriptional subunits. Mutations in the CARD family member, CARD14, have been identified in patients with the inflammatory skin diseases psoriasis and pityriasis rubra pilaris. Here, we describe that the gene coding for another CARD scaffold protein, CARD11, is mutated in more than 38 /0 of 111 cSCCs, and show that novel variants outside of the coiled-coil domain lead to constitutively activated NF-kappa B signaling. CARD11 protein expression was detectable in normal skin and increased in all cSCCs tested. CARD11 m RNA levels were comparable with CARD14 in normal skin and CARD11 mRNA was increased in cSCC. In addition, we identified CARD11 mutations in peritumoral and sun-exposed skin, suggesting that CARD11-mediated alterations in NF-kappa B signaling may be an early event in the development of cSCC.
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