UZ Leuven

A low UVB dose, with the potential to trigger a protective p53-dependent geneprogram, increases the resilience of keratinocytes against future UVB insults. Decraene D, Smaers K, Maes D, Matsui M, Declercq L, Garmyn M.   J Invest Dermatol2005;125(5):1026-31. Abstract: One protein central in the response of human keratinocytes to ultraviolet B damage is p53. By transactivating genes involved in either cell cycle arrest or DNA repair, p53 has a leading role in the recovery from this damage. Considering this role, we wished to investigate whether the triggering of a p53-dependent gene program by repetitive ultraviolet B (UVB) exposure can induce an adaptive response in human skin cells. In particular, we examined two p53-target genes, p21/WAF1 and p53R2, with a crucial role in p53-induced cell cycle arrest and p53-induced DNA repair respectively. Exposure to a mild UVB dose was able to induce an adaptive response in human keratinocytes,leading to increased survival of cells that maintain their capacity to repair DNA damage upon exposure to apoptotic doses of UVB. Our study indicates that this adaptation response is only achieved if the interval between subsequent UVB insults allows sufficient time for the p53-induced protective gene program to be induced. Our results also demonstrate that small but quickly recurring UVB exposures are as harmful as one intense, continual exposure to UVB irradiation. Future research will be oriented toward investigating alternative ways to induce an adaptive response without pre-exposing the cells to UV.

Casecontrol study to identify melanoma risk factors in the Belgian population: the significance of clinical examination. Nijsten T, Leys C, Verbruggen K, Verlinden V, Drieghe J, Stas M, Lambert J, DeGreef H, Garmyn M. J Eur Acad Dermatol Venereol 2005;19(3):332-9. Abstract: BACKGROUND: Although numerous studies have evaluated risk factors associated with cutaneous malignant melanoma (CMM), no such study has been carried out in Belgium. OBJECTIVES: To identify individuals who are at high risk of developing malignant melanoma in Belgium, which could enhance the efficacy of screening interventions and avoid unnecessary skin inspections. STUDY DESIGN/SETTING/ SUBJECTS: We prospectively included patients who were diagnosed with invasive malignant melanoma between 1998 and 2001 at the Department of Dermatology in a case-control study. Controls were selected from the outpatient dermatology clinic. Participants were interviewed and clinically examined by a dermatologist. We asked questions concerning most known risk factors associated with malignant melanoma such as phenotypical and skin characteristics, and environmental and lifestyle exposures. To adjust for confounding variables and to estimate odds ratios (ORs) and 95% confidence intervals (CIs), a multivariate model was used. RESULTS: Although sunburn in childhood and substantial occupational solar exposure were modestly, but significantly, associated with malignant melanoma risk, clinical examination yielded several stronger risk factors. In a multivariate model, which adjusted for age, gender and skin phototype, phenotypical characteristics such as skin, hair and eye colour were significantly associated with the development of malignant melanoma. In the multivariate model, people with three or more atypical naevi were at more than 10-fold risk of developing a malignant melanoma (> or = 3 atypical naevi; adjusted OR = 11.40, 95% CI = 4.79-17.53) compared to those without an atypical naevus. The presence of one or more palpable naevi on the upper extremities or having solar lentigines increased the odds of developing malignant melanoma at least twofold. CONCLUSIONS: In Belgium, risk factors associated with malignant melanoma appear to be in accordance with previous studies. To assess peoples’ risk profile, clinical skin examination is likely to yield the most important sporadic malignant melanoma risk factors. Therefore, focusing screening campaigns on individuals with predefined findings on skin self-examination may increase its efficacy.

AKT status controls susceptibility of malignant keratinocytes to the early-activated and UVB-induced apoptotic pathway. Decraene D, Van Laethem A, Agostinis P, De Peuter L, Degreef H, Bouillon R, Garmyn M. J Invest Dermatol 2004;123(1):207-12. Abstract: In previous work, we have described an early-activated and ultraviolet B (UVB)-induced apoptotic pathway in human keratinocytes, which can be completely inhibited by AKT activation. We now compared this response of primary human keratinocytes with the response of two p53-mutated squamous cell carcinoma (SCC)-derived cell lines (A431 and A253) to an apoptotic UVB dose. In these cell lines, both the basal AKT phosphorylation status and the apoptotic response to UVB diverged strongly from the response of healthy primary keratinocytes. Even more, a remarkable correlation was found between the two. Although a constitutive dual osphorylation of AKT rendered the A253 SCC cell line completely resistant to the early-activated and UVB-induced apoptotic pathway, deficient T308 phosphorylation of AKT in the SCC cell line A431 led to a greatly augmented sensitivity to the early-activated, UVB-induced apoptotic pathway. These results indicate that the preservation of a healthy AKT pathway is essential for a wild-type UVB-induced apoptotic response in skin, and suggest that AKT-mediated dysregulation of the early-activated apoptotic response to UVB is an important event in the oncogenic transformation of keratinocytes.

A synthetic superoxide dismutase/catalase mimetic (EUK-134) inhibits membrane-damage-induced activation of mitogen-activated protein kinase pathways and reduces p53 accumulation in ultraviolet B-exposed primary human keratinocytes. Decraene D, Smaers K, Gan D, Mammone T, Matsui M, Maes D, Declercq L, Garmyn M.J Invest Dermatol 2004;122(2):484-91. Abstract: Salen-manganese complexes exhibit powerful superoxide dismutase and catalase activity, with pharmacologic efficacy in several oxidative-stress-associated disease models. Ultraviolet (UV) B not only induces direct DNA damage, but also generates oxidative stress. EUK-134, a salen-manganese complex, might therefore confer a direct protection against UVB-induced oxidative stress and consequently alleviate UVBdamage-induced signal transduction. We investigated the effect of EUK-134 on the UVB-induced accumulation and stabilization of the p53 protein. p53 plays a central role in the UVB response, both as sensor of UVB damage and as a mediator of a protective response. Cells treated with EUK-134 before UVB irradiation showed a significantly lower accumulation of the p53 protein in a concentration-dependent fashion. Furthermore, EUK-134 severely reduced N-terminal phosphorylation of p53. The extracellular signalregulated kinase ERK and the stress-activated kinases JNK and p38 have been implicated in the UVB-induced N-terminal phosphorylation and accumulation of p53. Pre-treatment with EUK-134 inhibited the UVB-induced activation of these mitogen-activated protein kinase (MAPK) pathways. We hypothesize that EUK-134, by direct protection of the membrane from UVB-induced oxidative damage, reduces oxidative stress induced MAPK signaling and consequently lowers the level of p53 induction. The protection conferred by EUK-134 resulted in a significant increase in cell survival following UVB irradiation.

Insulin-like growth factor-1-mediated AKT activation postpones the onset of ultraviolet B-induced apoptosis, providing more time for cyclobutane thymine dimer removal in primary human keratinocytes. Decraene D, Agostinis P, Bouillon R, Degreef H, Garmyn M. J Biol Chem 2002;277(36):32587-95. Epub 2002 Jun 17. Abstract: Insulin-like growth factor-1 (IGF-1) acts as a potent survival factor in numerous cell lines, primarily through activation of the AKT signaling pathway. Although some targets of this pathway have known nti-apoptotic functions, its relationship with the improved survival of cells after exposure to environmental stresses, including UVB, remains largely unclear. We report that in growth factor-deprived keratinocytes, IGF-1 significantly and consistently delayed the onset of UVB-induced apoptosis by >7 h. This delay allowed IGF-1-supplemented keratinocytes to repair significantly more cyclobutane thymine dimers than their growth factor-deprived counterparts. This increase in cyclobutane thymine removal resulted in enhanced survival if the amount of DNA damage was not too high. To increase cell survival after UVB irradiation, IGF-1 supplementation was required only during this initial time period in which extra repair was executed. Finally, we show that IGF-1 mediated this delay in the onset of UVB-induced apoptosis through activation of the AKT signaling pathway. We therefore believe that the AKT signaling pathway increases cell survival after a genotoxic insult such as UVB irradiation not by inhibiting the apoptotic stimulus, but only by postponing the induction of apoptosis, giving the DNA repair mechanism more time to work.

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