Cancer

ORIGINAL ARTICLE

UVB-Induced Activation of NF-jB is Regulated by the IGF-1R and Dependent on p38 MAPK
Davina A. Lewis1 and Dan F. Spandau1,2
To manage the frequent exposure to carcinogenic UVB wavelengths found in sunlight, keratinocytes have extensive protective measures to handle UVB-induced DNA damage. Recent in vitro evidence and epidemiological data suggest that one possible protectivemechanism is dependent on the functional status of the IGF-1R signaling network. A second important signaling pathway regulating the response of keratinocytes to UVB involves the activation of the NF-kB transcription factor. Although it is clear that proper functioning of both the IGF-1R and NF-kB signaling networks are critical for the appropriate response of keratinocytes to UVB irradiation, itis currently uncertain if these two pathways interact. We now demonstrate that the activation of the NF-kB transcription factor by UVB is altered by the functional status of the IGF-1R. In the absence of ligand-activated IGF-1R, UVB-induced NF-kB consisted primarily of p50:p50 homodimers. Furthermore, the p38 kinase MAPK directs the subunit composition of NF-kB following UVB irradiation, mostlikely in an IGF-1R-dependent manner. We hypothesize that UVB irradiation leads to an activated p38 MAPK that is regulated in an IGF-1R-dependent manner, leading to NF-kB p50:RelA/p65 activation and a survival phenotype. In the absence of ligand-activated IGF-1R, UVB irradiation leads to the induction of NF-kB p50:p50 homodimers and a p38-dependent increased susceptibility to apoptosis.
Journal ofInvestigative Dermatology (2008) 128, 1022–1029; doi:10.1038/sj.jid.5701127; published online 6 December 2007

INTRODUCTION The primary environmental factor that influences the development of skin cancer is exposure to sunlight, particularly wavelengths in the UVB spectrum (Kripke, 1999). When the epidermis is exposed to UVB, the genomes of cutaneous keratinocytes become damaged (Mullenders etal., 1997). If UVB-induced DNA damage is allowed to persist in keratinocytes, alterations (or mutations) in genes will accumulate and cause these keratinocytes to deviate from the normal process of differentiation. This deviation from normal differentiation could eventually lead to a number of proliferative diseases, including basal cell carcinoma and squamous cell carcinoma (Yuspa and Dlugosz,1991). Fortunately, keratinocytes have extensive protective measures to handle UVB-induced DNA damage (Hainaut, 1995). Recent in vitro evidence (Kuhn

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Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA and 2Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA Correspondence: Dr Dan F. Spandau,Medical Library and Research Building, Indiana University Medical Center, 975 W. Walnut Street, Room 349, Indianapolis, Indiana 46202-5121, USA. E-mail: dspanda@iupui.edu Abbreviations: ASK1, apoptosis signal-regulating kinase 1; DEVD-AMC, aspartic acid-glutamic acid-valine-aspartic acid-aminomethylcoumarin; EMSA, electrophoretic mobility shift assay; ERK, extracellular-regulated kinase; HEPES,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; IGF-1R, IGF-1 receptor; JNK, jun N-terminal kinase; MAPK, mitogen-activated protein kinase; OCT-1, octomer-binding protein-1; PIPES, piperazine-1, 4-bis(2-ethanesulfonic acid); TNFa, tumor necrosis factor-a Received 17 May 2007; revised 2 August 2007; accepted 13 August 2007; published online 6 December 2007

et al., 1999) and epidemiologicaldata (Chuang et al., 2005) suggest that one possible protective mechanism involves the IGF-1 receptor (IGF-1R) signaling network. When normal human keratinocytes are grown in vitro, activated IGF-1Rs protect keratinocytes from UVB-induced apoptosis; however, although UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication (Kuhn et al., 1999)....