UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis

Abstract

The UVB component of the solar spectrum induces DNA lesions that, in the absence of error-free DNA repair, may give rise during DNA replication to mutations in caretaker and gatekeeper genes. The DNA repair genes are the best candidates for caretaker genes as exemplified by the human hereditary xeroderma pigmentosum (XP) syndrome. Cultured XP cells are hypermutable after UVB irradiation. This increased mutation frequency is also found in gatekeeper genes, which govern signalling pathways implicated in the control of cellular proliferation, differentiation and survival of human epidermal keratinocytes. We describe and discuss the role of mutated gatekeeper genes in five specific signalling pathways which have been implicated in skin carcinogenesis. The pathways we focus on in this review are: (i) P16(INK4A)-CDK4/6-RB; (ii) P14(ARF)-HDM2-P53; (iii) Sonic hedgehog (SHH)/GLI; (iv) WNT/beta-catenin; and (v) Bone Morphogenetic Protein (BMP)/SMAD. 70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs). In XP cancers, the typically UVB-induced CC to TT tandem transitions represent approximately 60% of total mutations compared to 10-15% in skin tumours from DNA repair-proficient patients. Acquired activation of the pathways described herein can alter proliferation and differentiation of keratinocytes, allowing a damaged cell to replicate and give rise to mutated daughter cells, then eventually to the development of the carcinogenic process following clonal selection.

Transcriptional profiles of unirradiated or UV-irradiated human cells expressing either the cancer-prone XPB/CS allele or the noncancer-prone XPB/TTD allele

“…Its activation and accumulation is triggered by a variety of stress signals, which relies on an autoregulatory loop. In fact, it is well known that after the stress signalling, the p53 protein becomes more stable and accumulates (Ehrhart et al, 2003). The UVC-p53 modulation found in XP/CS is the first observation of transcriptional regulation of this protein after a stress situation in DNA repair-deficient cells.…”

“…Cyclin D1 has an important role in the progression of cell cycle. It associates with cyclin-dependent kinases (CDK) CDK4 and CDK6 to phosphorylate the pRB protein during the G1 phase (Ehrhart et al, 2003).…”

CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice

“…Female breeders (6)(7) weeks old) of p53 -/-/ C57BL/6J strain were purchased from the Jackson Laboratory and were acclimatized for 1 week before being recruited to breeding. The male breeders of SKH-1 hairless strain (5-6 weeks old) were purchased from Charles River Laboratories and also acclimatized for a week as described earlier.…”

“…p53 mutations occur in the majority of SCCs, basal cell carcinomas, actinic keratoses, and perilesional nontumor skin adjacent to these lesions. These mutations are detectable early in the development of UVB-induced NMSCs (7,8). In murine models, UVB-associated p53 gene mutations also contribute to tumor development and are C to T and CC to TT transitions at dipyrimidine sites.…”

Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

“…25 In the above example, a possible explanation is that GK protein overexpression may be not only tolerated but also selected in the presence of a block affecting heterologous TSGs. 26,27 Consistent with this, CT inactivation is a common tumorigenetic event predisposing to GK mutation; 28 for example, repair deficiency (for example, microsatellite instability caused by mismatch repair gene inactivation) may lead to secondary mutations (for example, frameshifts) affecting GKs or POs in preinvasive tissues. 29,30 Moreover, as repair genes are involved in afferent sensing of DNA damage, 31,32 CT inactivation in tumors could also bias GK function towards a pro-mitogenic phenotype by raising the apoptotic threshold.…”