Enhanced skin carcinogenesis in cyclin D1-conditional transgenic mice: cyclin D1 alters keratinocyte response to calcium-induced terminal differentiation.
Cyclin D1 is a critical gene involved in the regulation of progression through the G(1) phase of the cell cycle, thereby contributing to cell proliferation. Gene amplification and abnormal expression of Cyclin D1 have been described in several human cancers. To understand their biological significance in skin carcinogenesis, we established Cyclin D1-conditional transgenic mice with C57BL/6J background, in which skin-specific overexpression of Cyclin D1 transgene was observed. The mice were subjected to dimethylbenz[a]anthracene complete skin carcinogenesis studies. After 40 weeks of repeated administration of dimethylbenz[a]anthracene on the skin (once a week), all of the mice with high Cyclin D1 expression had papillomas, whereas only 9.5% of the control mice without the transgene developed papillomas. Primary cultured keratinocytes with induced Cyclin D1 transgene expression showed resistance to calcium-induced terminal differentiation and continued to replicate in vitro. These results clearly provide us with direct experimental evidence that overexpression of CyclinD1 induces excessive dermal cell proliferation via the altered differentiation state of keratinocytes. The conditional transgenic mice described here provide excellent in vivo and in vitro model systems to understand the role of cyclin D1 and deregulation of the cell cycle in carcinogenesis.
Yamamoto
Hanako
H
National Cancer Center Research Institute, Section for Studies on Metastasis, Tokyo 104-0045, Japan.
Ochiya
Takahiro
T
Takeshita
Fumitaka
F
Toriyama-Baba
Hiroyasu
H
Hirai
Kotaro
K
Sasaki
Hideo
H
Sasaki
Hiroki
H
Sakamoto
Hiromi
H
Yoshida
Teruhiko
T
Saito
Izumu
I
Terada
Masaaki
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002273:Carcinogens; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D002273:Carcinogens; D019938:Cyclin D1; D015127:9,10-Dimethyl-1,2-benzanthracene; D002118:Calcium