Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control

Abstract

Analysing cylindromatosis and the associated defects in the CYLD gene is providing novel insights into the molecular principles of epithelial growth control and carcinogenesis in, and beyond, the skin. In this review, we summarize the histopathology and histogenesis of cylindromas, and the available genetic information on patients with these skin appendage tumors. Focusing on recent data concerning the normal functions and signaling interactions of the CYLD gene product, we explain how CYLD interferes with TNF-alpha or TLR-mediated signaling as well as with JNK or NF-kappaB-dependent p65/50 signaling to limit inflammation. In addition, we delineate how CYLD interferes with activation of the proto-oncogene Bcl(3) and with cyclin D1 expression to limit tumorigenesis, and chart how tumor growth-promoting agents or UV light and inflammatory mediators can activate CYLD. We argue that these recent insights into CYLD function and cylindroma pathogenesis may lead to the development of novel molecular strategies for cancer prevention and treatment.

Skin type spiradenoma of the parotid gland with malignant transformation

“…CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB. Loss of the deubiquitinating activity of CYLD is correlated with tumorigenesis [13]. Various mutations in the CYLD gene have been found in individuals affected with BSS [14][15][16][17][18].…”

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

“…Thus, mice deficient in CYLD are more susceptible to develop chemically induced skin tumors (Massoumi et al, 2006;Massoumi and Paus, 2007). In this case, the loss of CYLD in keratinocytes was linked to hyperproliferation and elevation in cyclin D1 levels because of increased nuclear activity of Bcl-3-associated NF-kB p50 and p52 and is independent of the classical p65/NF-kB pathway (Massoumi et al, 2006).…”

Bcl-3, a multifaceted modulator of NF-κB-mediated gene transcription

“…Bcl-3 was also recently shown to be K-63 polyubiquitinated. This type of ubiquitination is necessary for the nuclear translocation of Bcl-3 in keratinocytes and B cells [46][47][48][49]. More research is needed to identify additional enzymes that post-translationally modify and thus regulate Bcl-3's function.…”

“…Epithelial cancer cells have elevated levels of Bcl-3 and p50 homodimer [57]. Cylindromas are also associated with Bcl-3 as they are caused by mutations in the CYLD gene, which has been shown to inhibit Bcl-3 nuclear translocation in certain cell type [16,[46][47][48][49]. A loss of function mutation in CYLD results in elevated levels of nuclear Bcl-3.…”