Central role of p53 in the suntan response and pathologic hyperpigmentation.
UV-induced pigmentation (suntanning) requires induction of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion by keratinocytes. alpha-MSH and other bioactive peptides are cleavage products of pro-opiomelanocortin (POMC). Here we provide biochemical and genetic evidence demonstrating that UV induction of POMC/MSH in skin is directly controlled by p53. Whereas p53 potently stimulates the POMC promoter in response to UV, the absence of p53, as in knockout mice, is associated with absence of the UV-tanning response. The same pathway produces beta-endorphin, another POMC derivative, which potentially contributes to sun-seeking behaviors. Furthermore, several instances of UV-independent pathologic pigmentation are shown to involve p53 "mimicking" the tanning response. p53 thus functions as a sensor/effector for UV pigmentation, which is a nearly constant environmental exposure. Moreover, this pathway is activated in numerous conditions of pathologic pigmentation and thus mimics the tanning response.
Cui
Rutao
R
Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Widlund
Hans R
HR
Feige
Erez
E
Lin
Jennifer Y
JY
Wilensky
Dara L
DL
Igras
Viven E
VE
D'Orazio
John
J
Fung
Claire Y
CY
Schanbacher
Carl F
CF
Granter
Scott R
SR
Fisher
David E
DE
D000818:Animals; D017209:Apoptosis; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D052816:Foreskin / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53; D006801:Humans; D017495:Hyperpigmentation / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D012880:Skin Pigmentation; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation; D000521:alpha-MSH / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000521:alpha-MSH; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin