Overexpression of Cdk6–cyclin D3 highly sensitizes cells to physical and chemical transformation

Abstract

Virtually all mammalian cells express two seemingly redundant cyclin-D-dependent kinases (Cdk4 and Cdk6) and three partner cyclins (D1, D2 and D3) essential for the G 1 -S transition, with predominant expression of Cdk4 and D1 in mesenchymal cells and Cdk6 and D3 in hematopoietic cells. We recently found two novel functions for Cdk6 executed in fibroblasts although unlike Cdk4 it is dispensable for their proliferation. In the rat fibroblast NRK-49F cells, oncogenic stimulation recruits Cdk6 to participate in a step of the cell cycle start that seems to be critical for anchorage-independent S-phase onset. Among the kinase-D-type cyclin combinations, the Cdk6-cyclin-D3 complex has a unique ability to evade inhibition by cyclin-dependent kinase inhibitors and thereby control the cell's proliferative competence under growth-suppressive conditions. We describe here that 2-5-fold overexpression of both Cdk6 and D3 enhances by 5 Â 10 3 -10 6 -fold the susceptibility of the BALB/c3T3 and C3H10T1/2 mouse fibroblast lines to ultraviolet irradiation-as well as 3-methylcholanthrene-induced transformation. This result suggests that deregulated expression of Cdk6 and cyclinD3 may predispose cells to malignant transformation, supporting the recent finding that cyclin D3 activated by chromosomal rearrangement is the causative gene of non-Hodgkin B lymphoma, in which Cdk6 is the major partner kinase.

P38SAPK2 phosphorylates cyclin D3 at Thr-283 and targets it for proteasomal degradation

“…A recent report indicates that cyclin D3 is also required in mouse and human T-cell malignances (Sicinska et al, 2003). Moreover, cyclin D3 in collaboration with cdk6 enhances transformation sensitivity in a number of mouse fibroblast cell lines (Chen et al, 2003). Thus, alterations of the mechanisms involved in the regulation of cyclin D3 levels play an import role in oncogenesis.…”

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

“…2. Shortly after addition of P276-00 to H-460 cells (3,6,9,12, and 24 h), significant reduction in enzyme activity was seen at 6 h onward (Fig. 2).…”

G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia

“…Among the genes differentially expressed at higher levels in HOX11 þ THY137 cells were c-myc itself and the E2F target cyclin D3 (CCND3; Figure 2a), deregulated expression of which may predispose to malignant transformation (Sonoki et al, 2001;Chen et al, 2003).…”