Differential effects of 5-aminolaevulinic acid photodynamic therapy and psoralen + ultraviolet A therapy on p53 phosphorylation in normal human skin in vivo
University of Dundee, Dundee, Scotland, United Kingdom British Journal of Dermatology
(Impact Factor: 4.28).
12/2005; 153(5):1001-10. DOI: 10.1111/j.1365-2133.2005.06922.x
Phosphorylation of the tumour suppressor p53 by the CK2/FACT pathway plays a central role in suppressing ultraviolet (UV)-induced skin cancer in animal models. Although p53 protein stabilization is induced after solar-simulated irradiation of human skin in vivo, p53 phosphorylation has not been defined.
To investigate the effects of clinically effective treatments for skin diseases including psoralen + UVA (PUVA) and photodynamic therapy (PDT) on p53 phosphorylation to determine whether the tumour-suppressing p53 kinase pathways are activated upon use of these therapies.
We used antibodies to the ATM/ATR and CK2/FACT phosphorylation sites on p53.
We found that p53 activation was induced selectively by PUVA treatment, while 8-oxo-7,8-dihydroguanine DNA damage was induced selectively by 5-aminolaevulinic acid (ALA)-PDT treatment. Importantly, PUVA treatment resulted in p53 kinase activation, as defined by p53 modification at AT (serine-15) and CK2/FACT (serine-392) sites within the proliferative compartment.
These data demonstrate that PUVA provokes accumulation and phosphorylation of p53 by AT and CK2/FACT within critical proliferative focal points (as determined by p63 colocalization studies) where DNA damage may lead to tumorigenesis. PDT is mechanistically distinct in that there is a lower level of induction of p53 expression with no evidence of AT- or CK2/FACT-mediated phosphorylation. This suggests that the type of DNA damage created by the reactive oxygen species generated by ALA-PDT does not induce the p53 pathway classically required for the repair of DNA photoadducts induced by UV.
Available from: Gwo-Tarng Sheu
- "Psoralen promoted osteoblast differentiation by activation of BMP signaling and could be a potential anabolic agent to treat patients with bone loss-associated disease (Tang et al., 2011). Furthermore, psoralen can form DNA interstrand cross-links upon activation with UVA radiation, and the cross-links repair may involve DNA double strand breaks and/or recombination (Finlan et al., 2005; Toyooka and Ibuki, 2009). However, effects of psoralen on anti-multidrug resistance and the molecular mechanisms remain poorly unknown. "
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