Cyclin D3 deficiency inhibits skin tumor development, but does not affect normal keratinocyte proliferation.

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Version: Final published version
Serval ID
serval:BIB_5ED9C32DAA5F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cyclin D3 deficiency inhibits skin tumor development, but does not affect normal keratinocyte proliferation.
Journal
Oncology letters
Author(s)
Lee S.H., Wang X., Kim S.H., Kim Y., Rodriguez-Puebla M.L.
ISSN
1792-1074 (Print)
ISSN-L
1792-1074
Publication state
Published
Issued date
09/2017
Peer-reviewed
Oui
Volume
14
Number
3
Pages
2723-2734
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Rearrangement and amplification of the D-type cyclin genes have been reported in human cancer. Previous studies have demonstrated that Ras-mediated skin tumorigenesis depends on pathways that act through cyclin D1 and D2; however, the role of cyclin D3 remains unknown. The present study demonstrates that cyclin D3 ablation does not affect keratinocyte proliferation, but instead increases apoptosis levels in the bulge region of the hair follicle. Consequently, cyclin D3 ablation reduces skin papilloma development in a Ras-dependent carcinogenesis model. Previous results revealed that cyclin D3 preferentially binds to cyclin-dependent kinase 6 (CDK6) in mouse keratinocytes and transgenic expression of CDK6 (K5CDK6 mice) inhibits skin tumor development. Thus, we hypothesized that the inhibitory effect of CDK6 is dependent on cyclin D3 expression. To test this hypothesis, a mouse model that overexpresses CDK6 and does not express cyclin D3 (K5CDK6/cyclin D3-/- compound mouse) was developed. Biochemical analysis of the epidermis of K5CDK6/cyclin D3-/- mice revealed that cyclin D3 ablation resulted in increased expression of cyclin D1 protein, with a consequent elevation in the level of CDK6/cyclin D1 and CDK4/cyclin D1 complexes. These findings were concurrent with the increase skin papilloma malignant progression observed in K5CDK6/cyclin D3-/- mice. In summary the absence of cyclin D3 led to fewer number of papillomas in cyclin D3-ablated mice than in the wild-type owing to increased apoptosis, suggesting that alterations in cell survival are a crucial mechanism for crippling cellular defense against neoplasia. The results of the current study also suggest that although cyclin D3 expression does not alter the tumor suppressive role of CDK6 in skin carcinogenesis, the compensatory increase in cyclin D1 can shift the balance towards malignant progression.

Keywords
cell cycle, cyclin D3, cyclin-dependent kinase 6, epidermis, papillomas, skin
Pubmed
Web of science
Open Access
Yes
Create date
25/09/2017 17:02
Last modification date
20/08/2019 14:16
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