Tumorigenesis facilitated by Pten deficiency in the skin: evidence of p53-Pten complex formation on the initiation phase.
Pten, a tumor suppressor gene, is mutated in various human cancers and in hereditary cancer syndromes, such as Cowden disease. We have previously developed a knockout mouse in which Pten is specifically disrupted in the skin, resulting in hyperproliferation and spontaneous tumorigenesis of the skin keratinocytes. In this study, we further clarified the effects of Pten deficiency in tumorigenesis, by using a two-step model in intact skin of Pten knockout mouse. Although the conventional protocol requires serial exposures to DMBA and TPA, mice deficient for Pten developed skin papilloma within 6 weeks after a single exposure to DMBA, indicating that loss of Pten has a tumor-promoting effect. Serial exposure to DMBA-TPA ointments produced 10-fold more papillomas in the skin of knockout mice than in the wild-type counterpart, suggesting an increased rate of initiation. Therefore, we precisely examined the effect of DMBA. This treatment was highly apoptotic in wild-type mice, whereas the number of apoptotic cells was diminished in Pten-deficient skin. Moreover, primary keratinocytes isolated from Pten-deficient mice were also resistant to the apoptotic effect of DMBA. The status of p53, Pten proteins and downstream targets of p53, such as p21, 14-3-3, and Reprimo, were also examined, and we found that accumulation of p53 protein and up-regulation of p53 targets were delayed in Pten-knockout skin. These observations suggest that Pten is involved in rapid recruitment of p53 in the tumor initiation phase.
Department of Social and Environmental Medicine, Osaka University, Suita, 565-0871, Japan.
Nobuyasu
N
Komazawa
Akira
A
Suzuki
Shigetoshi
S
Sano
Kyoji
K
Horie
Nariaki
N
Matsuura
Tak Wah
TW
Mak
Toru
T
Nakano
Junji
J
Takeda
Gen
G
Kondoh
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000633:toxicity; D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D004249:DNA Damage; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D015603:Keratinocytes; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase; D010212:Papilloma / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics* / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics* / Q000494:pharmacology
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase