Combined effect of cyclin D3 expression and abrogation of cyclin D1 prevent mouse skin tumor development.
We have previously demonstrated that ras-mediated skin tumorigenesis depends on signaling pathways that act preferentially through cyclin D1 and D2. Interestingly, the expression of cyclin D3 inhibits skin tumor development, an observation that conflicts with the oncogenic role of D-type cyclins in the mouse epidermis. Here, we show that simultaneous up and downregulation of particular members of the D-type cyclin family is a valuable approach to reduce skin tumorigenesis. We developed the K5D3/cyclin D1(-/-) compound mouse, which overexpresses cyclin D3 but lacks expression of cyclin D1 in the skin. Similar to K5D3 transgenic mice, keratinocytes from K5D3/cyclin D1(-/-) compound mice show a significant reduction of cyclin D2 levels. Therefore, this model allows us to determine the effect of cyclin D3 expression when combined with reduced or absent expression of the remaining two members of the D-type cyclin family in mouse epidermis. Our data show that induced expression of cyclin D3 compensates for the reduced level of cyclin D1 and D2, resulting in normal keratinocyte proliferation. However, simultaneous ablation of cyclin D1 and downregulation of cyclin D2 via cyclin D3 expression resulted in a robust reduction in ras-mediated skin tumorigenesis. We conclude that modulation of the levels of particular members of the D-type cyclin family could be useful to inhibit tumor development and, in particular, ras-mediated tumorigenesis.
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
Xian
X
Wang
Christopher
C
Sistrunk
Paula L
PL
Miliani de Marval
Yongbaek
Y
Kim
Marcelo L
ML
Rodriguez-Puebla
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056742:Cyclin D2 / Q000378:metabolism; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden
C530105:Ccnd1 protein, mouse; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D019938:Cyclin D1; D015127:9,10-Dimethyl-1,2-benzanthracene; D015689:Oncogene Protein p21(ras)