Expression of cyclins and cdks throughout murine carcinogenesis

The overexpression and/or amplification of cell cycle regulating genes is a n important factor in the progression of cancer. Recent attention has been focused on several cyclin and cdks genes whose expression were increased in many types of tumor. In this study, we investigated the expression kinetic s of cyclins A, B, D1, E and cdks 1, 2, 4, 6 by RT-PCR coupled with densito metry and correlated to the growth fraction (percentage of S cells). This a nalysis was performed using an experimental murine leukemic model, generate d by in vivo administration of murine clonogenic cells Wehi-3b injected int o balb-c mice, Differential expression of cyclins and cdks was observed bet ween normal and tumoral cells with different patterns of expression between G1 and G2M cyclins-cdks. G1 cyclins cdks expression was significantly incr eased in tumor cells when compared to normal cells. In the same manner, G2M cyclins cdks expression was only observed in tumor cells at a lower level than for G1 cyclins cdks, but not detected in normal cells. These differenc es correlated with the growth fraction for both the G1 cyclins cdks (r=0.91 , 0.94, 0.85, 0.90 and 0.96 for cyclin D1, cyclin E, cdk2, cdk4 and cdk6, r espectively) and the G2M cyclins cdks (r=0.96, 0.97 and 0.93 for cyclins A, B and cdk1 respectively). Analysis of cyclins cdks expression kinetics dur ing tumoral progression shows that cyclins A, B and cdk1 were expressed fro m the 12th day on of disease, increased until the death of the animals and correlated with the growth fraction (r=0.94, 0.95 and 0.97 for cyclins A, B and cdk1 respectively) (n=20). Overexpression of other cyclins cdks were o bserved, from the 6th day on for cyclin D1, the 12th day for cdk2 and cdk4, the 15th day for cdk6 and the 20th day for cyclin E. These increases persi sted during tumoral progression and correlated with the growth fraction (r= 0.85, 0.94, 0.93, 0.96, and 0.98 for cyclin D1, cyclin E, cdk2, cdk4, and c dk6, respectively) (n=20). Our results demonstrated that G1 and G2-M cyclin s cdks mRNA levels were increased at approximately the same time of maximal tumor growth. Only cyclin D1 overexpression occured at the initiation of t umoral development, and could therefore be considered as an early marker of cell proliferation.