An Van Laethem

Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes

This study establishes that activation of p38 MAPK by UVB represents a crucial signal required for the conformational change and translocation of Bax to the mitochondria in human keratinocytes. UVB‐induced Bax translocation and mitochondrial cytochrome c release, which precede caspase activation and other endpoints of the apoptotic program such as chromatin fragmentation and loss of mitochondrial transmembrane potential, are blocked by genetic or pharmacological inhibition of the p38α MAPK. Inhibition of p38 MAPK strongly reduces the UVB‐induced formation of sunburn cells and blocks Bax conformational change both in cultured human keratinocytes and in human skin, providing clear evidence for the physiological role of the p38 MAPK‐Bax pathway in the removal of precancerous, UVB‐damaged keratinocytes. Furthermore, we show that Bcl‐2 overexpression, but not the pan‐caspase inhibitor zVAD‐fmk, blocks Bax conformational change and its subsequent translocation downstream of p38 MAPK. These data indicate that the activation of p38 MAPK by UVB engages a caspase‐independent death signal leading to mitochondrial membrane permeabilization and apoptosis in human keratinocytes and suggest that p38 MAPK might have a preventive role in the process of photocarcinogenesis.

New Strategies of Photoprotection

Adequate photoprotection is essential to control UV‐related disorders, including sunburn, photoaging and photocarcinogenisis. Sun avoidance, protection of skin with clothing, and sunscreens are presently the best way of photoprotection, assuming that they are used properly. However, new strategies, which are based on or make use of the endogenous protective response to UV light, may further improve currently used photoprotective means. The addition of repair enzymes and/or antioxidants has a positive effect on skins recovery from UV‐induced DNA‐damage. Several botanical agents, mainly vitamins and polyphenols, have shown to influence signal transduction pathways leading to photo‐protective effects. Also stimulation of endogenous UV‐response pathways via irradiation with a low UV dose or via simulation of UV‐induced DNA‐damage results in photo‐protective effects. Future research in this field and combination of different photoprotective strategies will hopefully lead to improved photoprotection.

Pathways involved in sunburn cell formation: deregulation in skin cancer

The incidence of squamous cell carcinoma of the skin is rising worldwide for decades. Chronic exposure to sunlight is the most important environmental risk factor for this type of skin cancer. This is predominantly due to the DNA damaging effect of ultraviolet-B (UVB) in sunlight. UVB induces also sunburn cells, i.e. apoptotic keratinocytes, which is a crucial protective mechanism against the carcinogenic effects of UVB irradiation. This process is regulated by a wide range of molecular determinants involved in the balance between pro- and anti-apoptotic pathways. Growing evidence suggests that the deregulation of this balance by chronic UVB irradiation, contributes to the development of skin cancer. This review gives a brief summary of major known pathways involved in the regulation of keratinocyte survival and cell death upon UVB damage and discusses the contribution of the deregulation of these cascades to photocarcinogenesis.

The Aryl Hydrocarbon Receptor: An Illuminating Effector of the UVB Response

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor that mediates most of the toxic and carcinogenic effects of drugs and environmental toxins collectively known as xenobiotics. Ligand activation of the AhR stimulates the transcription of genes that encode several xenobiotic-metabolizing enzymes. The molecular mechanisms and signaling pathways evoked by the activation of the AhR are becoming increasingly understood and underscore the participation of the AhR in crucial processes, including cellular stress response, proliferation, differentiation, inflammation, and carcinogenesis. Studies now implicate the AhR as an integral part of the multifaceted signal transduction pathway initiated by the exposure of keratinocytes to ultraviolet B radiation (UVB), which is the most ubiquitous hazard to human skin and the principal risk factor for skin cancer. Ligand-dependent activation of the AhR in the cytosol provides a molecular bridge that links cytoplasmic events to nuclear signals, thus unmasking a previously unknown role for this transcription factor in the complex cellular response to UVB.

A p38MAPK/HIF-1 Pathway Initiated by UVB Irradiation Is Required to Induce Noxa and Apoptosis of Human Keratinocytes

The signal transduction pathways leading to apoptosis of human keratinocytes responding to UVB irradiation are complex and not completely understood. Previously, we reported that in UVB-irradiated keratinocytes, p38(MAPK) instigates Bcl-2-associated X protein (Bax) activation and mitochondrial apoptosis. However, the molecular mechanism underlying the pro-apoptotic function of p38(MAPK) remained unclear. Here, we show that in UVB-treated human primary keratinocytes the activation of p38(MAPK) is necessary to upregulate Noxa, a BH3-only pro-apoptotic dominantly induced by UVB and required for apoptosis. Whereas p53-silencing was marginally cytoprotective and poorly affected Noxa expression, p38(MAPK) inhibition in p53-silenced keratinocytes or in p53(-/-) cells could still efficiently prevent Noxa induction and intrinsic apoptosis after UVB, indicating that p38(MAPK) signals mainly through p53-independent mechanisms. Furthermore, p38(MAPK) was required for the induction and activation of hypoxia-inducible factor 1 (HIF-1) in response to UVB, and HIF-1 knockdown reduced Noxa expression and apoptosis. In UVB-irradiated keratinocytes, Noxa targeted the anti-apoptotic myeloid cell leukemia sequence 1 (Mcl-1) for degradation, and small-interfering RNA (siRNA)-mediated knockdown of Noxa or p38(MAPK) inhibition restored levels of Mcl-1 and abolished apoptosis. Thus, the pro-apoptotic mechanisms orchestrated by p38(MAPK) in human keratinocytes in response to UVB involve an HIF-1/Noxa axis, which prompts the downregulation of anti-apoptotic Mcl-1, thereby favoring Bax-mediated mitochondrial apoptosis of UVB-damaged keratinocytes.