A darker side to p53.

The tumor suppressor protein p53 is activated inresponse to various types of cellular stress and DNAdamage, and regulates, chieﬂy through its activity as atranscription factor, genes implicated in apoptosis, DNArepair, cell cycle and senescence (Levine et al., 2006). In as much, functional p53 can tilt cell fate to surviveand repair damage or initiate the cell death program.P53 is often dysregulated in human tumors, includingskin cancer, where such mutations were shown toresult from sun exposure (Ananthaswamy et al., 1997). The work by Fisher’s group, sheds important new lightinto mechanisms underlying the protection of keratino-cytes by p53.A key factor in predicting the risk of developing skincancer is through determining an individual’s skin photo-type, i.e. skin color and ability to tan. Fair skinned indi-viduals, who sun burn easily and have an increasedpropensity to freckle rather than tan are at a higher riskof developing non-malignant skin cancers than individu-als with darker skin. This ability to tan is directly relatedto the synthesis of melanin by melanocytes, typicallyfound in the basal layer of the epidermis of vertebrateskin. Melanin is thought to play a photoprotective role inresponse to UV radiation by protecting the cell’s DNAfrom UV-induced mutations (Kobayashi et al., 1993). Melanin production is induced through the associationof a-melanocyte stimulating hormone (aMSH) with itsreceptor melanocortin-1 receptor (MC1R) (Garci´a-Borro´net al., 2005) expressed on the surface of melanocytes.Activation of MC1R ultimately leads to the activation ofmicrophthalmia-associated transcription factor (MITF)involved in the actual production of the pigmentenzymes (Rouzaud et al., 2005). aMSH is derived fromthe multi-component gene pro-opiomelanocortin(POMC), which also codes for adrenocorticotropic hor-mone (ACTH) and b-endorphin.D’Orazio et al. (2006) had previously demonstratedsigniﬁcant induction of a-MSH protein levels in kera-tinocytes, a key target of solar radiation, in responseto UV exposure and Corre et al. (2004) also highligh-ted a role for the USF transcription factor in POMCexpression in response to UV and p38 stress signa-ling. A closer look at the promoter region of thePOMC gene, from which a-MSH is derived, led Fisherand his colleagues (Cui et al., 2007) to identify a con-sensus binding sequence for p53, which is upregulat-ed by UV radiation. Cui et al. demonstrate a p53-dependent increase in a-MSH levels and consequentlyskin pigmentation suggesting a novel mechanism bywhich p53 protects keratinocytes from UV-radiationinduced DNA mutations.Cui et al. demonstrated that exposure to UV radiationin primary human keratinocytes and a mouse keratino-cyte cell line PAM212 caused an increase in the levelsof POMC protein expression as well as a 30-fold induc-tion of a-MSH secretion, in conjunction with the expec-ted increase in p53 protein levels. POMC induction afterUV radiation was p53 dependent since induction waslost in PAM212 cells expressing a dominant negativep53 allele and also in keratinocytes nullizygous for p53expression. The authors also constructed a series ofreporter constructs using the promoter region of thePOMC gene and showed that the p53 consensussequence was critical for the UV based inductionobserved. Using ChIP and electrophoretic mobility shiftanalysis, the authors demonstrated UV-induced DNA-binding of p53 to the POMC promoter region indicativeof p53s regulation of POMC in response to UV radi-ation.At the physiological level, mice lacking p53 did notappear visibly tanned at the ears or tail compared withmice expressing wild type p53 after prolonged UV expo-sure, which was conﬁrmed histologically by staining formelanin and POMC precursor. When discarded humanforeskin was exposed to UV radiation, the authorsshowed a sequential increase ﬁrst in the levels of p53protein, next a-MSH and ﬁnally MITF expression whichcorrelates well with their proposed signaling cascadeinvolving skin pigmentation.Cui et al. also demonstrated a possible role for p53in non-UV induced skin pigmentation by exposingPAM212 keratinocytes to etoposide, a DNA damagingagent known to induce p53, with a correlative increasein the levels of POMC levels. In vivo, when p53 wild