Distinct proliferative and transcriptional effects of the D-type cyclins in vivo

被引:68
作者
Mullany, Lisa K. [1 ,2 ]
White, Peter [3 ]
Hanse, Eric A. [2 ]
Nelsen, Christopher J. [2 ]
Goggin, Melissa M. [2 ]
Mullany, Joseph E. [2 ]
Anttila, Chelsea K. [2 ]
Greenbaum, Linda E. [4 ]
Kaestner, Klaus H. [3 ]
Albrecht, Jeffrey H. [1 ,2 ]
机构
[1] Hennepin Cty Med Ctr, Div Gastroenterol, Minneapolis, MN 55415 USA
[2] Minneapolis Med Res Fdn Inc, Minneapolis, MN USA
[3] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
[4] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA
关键词
cyclin D1; cyclin D2; cyclin D3; liver regeneration;
D O I
10.4161/cc.7.14.6274
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The D-type cyclins (D1, D2 and D3) are components of the cell cycle machinery and govern progression through G(1) phase in response to extracellular signals. Although these proteins are highly homologous and conserved in evolution, they contain distinct structural motifs and are differentially regulated in various cell types. Cyclin D1 appears to play a role in many different types of cancer, whereas cyclins D2 and D3 are less frequently associated with malignancy. In this study, we transiently expressed cyclin D1, D2 or D3 in hepatocytes and analyzed transcriptional networks regulated by each. All three D-type cyclins promoted robust hepatocyte proliferation and marked liver growth, although cyclin D3 stimulated less DNA synthesis than D1 or D2. Accordingly, the three D-type cyclins similarly activated genes associated with cell division. Cyclin D1 regulated transcriptional pathways involved in the metabolism of carbohydrates, lipids, amino acids, and other substrates, whereas cyclin D2 did not regulate these pathways despite having an equivalent effect on proliferation. Comparison of transcriptional profiles following 70% partial hepatectomy and cyclin D1 transduction revealed a highly significant overlap, suggesting that cyclin D1 may regulate diverse cellular processes in the regenerating liver. In summary, these studies provide the first comparative analysis of the transcriptional networks regulated by the D-type cyclins and provide insight into novel functions of these key cell cycle proteins. Further study of the unique targets of cyclin D1 should provide further insight into its prominent role in proliferation, growth and cancer.
引用
收藏
页码:2215 / 2224
页数:10
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