| First Author | Garc?a-Garc?a VA | Year | 2025 |
| Journal | Oncogene | Volume | 44 |
| Issue | 3 | Pages | 165-178 |
| PubMed ID | 39511409 | Mgi Jnum | J:360418 |
| Mgi Id | MGI:7834374 | Doi | 10.1038/s41388-024-03203-0 |
| Citation | Garcia-Garcia VA, et al. (2024) Nuclear versus cytoplasmic IKKalpha signaling in keratinocytes leads to opposite skin phenotypes and inflammatory responses, and a different predisposition to cancer. Oncogene |
| abstractText | IKKalpha is known as an essential protein for skin homeostasis. However, the lack of suitable models to investigate its functions in the skin has led to IKKalpha being mistakenly considered as a suppressor of non-melanoma skin cancer (NMSC) development. In this study, using our previously generated transgenic mouse models expressing exogenous IKKalpha in the cytoplasm (C-IKKalpha mice) or in the nucleus (N-IKKalpha mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKalpha differently regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, and for the cutaneous inflammatory response. In addition, each type of IKKalpha-transgenic mice shows different predisposition to the development of spontaneous NMSC. Specifically, N-IKKalpha mice display an atrophic epidermis with exacerbated terminal differentiation, signs of premature skin aging, premalignant lesions, and develop squamous cell carcinomas (SCCs). Conversely, C-IKKalpha mice, whose keratinocytes are nearly devoid of endogenous nuclear IKKalpha, do not develop skin SCCs, although they exhibit hyperplastic skin with deficiencies in terminal epidermal differentiation, chronic cutaneous inflammation, and constitutive activation of STAT-3 and NF-kappaB signaling pathways. Altogether, our data demonstrate that alterations in the localization of IKKalpha in the nucleus or cytoplasm of keratinocytes cause opposite skin changes and differentially predispose to the growth of skin SCCs. |
