Relationship of p53 mutations to epidermal cell proliferation and apoptosis in human UV-induced skin carcinogenesis.
Human skin is continually subjected to UV-irradiation with the p53 gene playing a pivotal role in repair of UV-induced DNA damage and apoptosis. Consequently, p53 alterations are early events in human UV-induced skin carcinogenesis. We studied 13 squamous cell carcinomas (SCC), 16 actinic keratoses (AK), 13 samples adjacent to an AK (chronically sun-damaged), and 14 normal-appearing skin samples for p53 mutation, p53 immunostaining (IHC), apoptosis (in situ TUNEL and morphology), and proliferation (PCNA). The frequency of p53 mutation increased from 14% in normal skin, to 38.5% in sun-damaged skin, 63% in AK, and 54% in SCC. p53 IHC increased similarly. Apoptosis (TUNEL) increased from 0.06 +/- 0.02%, to 0.1 +/- 0.2, 0.3 +/- 0.3, and 0.4 +/- 0.3 in normal skin, sun-damaged skin, AK, and SCC, respectively. Apoptosis was strongly correlated with proliferation (i.e., TUNEL and PCNA, r = 0.7, P < 0.0001), and proliferation was significantly increased in the progression from normal skin to SCC. Bax was significantly increased in SCC compared to AK. These data imply that apoptosis in samples with a high frequency of p53 mutation may not necessarily be p53-dependent. We suggest that there is a mechanism for apoptosis in response to increased cellular proliferation that is p53-independent.
Einspahr
J G
JG
The Arizona Cancer Center, College of Medicine, The University of Arizona, Tucson 85724, USA.
Alberts
D S
DS
Warneke
J A
JA
Bozzo
P
P
Basye
J
J
Grogan
T M
TM
Nelson
M A
MA
Bowden
G T
GT
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007642:Keratosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018807:Polymorphism, Single-Stranded Conformational; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014466:Ultraviolet Rays
D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53