Current Research
We recently
made critical findings on the anchorage-independent S phase
onset, the most fundamental phenotype of cancer cells that
underlies their metastatic capability. In addition to the
activation of Cdk4/6 and Cdk2, the expression of Cdc6, a key
factor essential for the activation of replication origins,
requires cell's anchorage to extracellular matrix or oncogenic
stimulation. Without anchorage or oncogenic stimulation, the
expression of Cdc6 is blocked by both transcriptional repression
and facilitated proteolytic degradation (49).
Most of our efforts, therefore, are being devoted to the understanding
of how Cdc6 expression is regulated by anchorage and oncogenic
signals.
Recently we found that among D-type cyclin (D1, D2, D3) and
partner kinase (Cdk4, Cdk6) combinations, the Cdk6-D3 complex
is unique and can evade inhibition by p27 and p21, consequently
enabling this complex to control proliferation competence
under growth-suppressive conditions. In fact, several fold
overexpression of Cdk6-D3 not only drastically reduces serum
requirement for proliferation, but also markedly enhances
proliferation to a much higher density. Moreover, in fibroblast
cell lines, Cdk6 is induced by growth factors whereas D3 is
constitutively expressed. These findings raise the possibility
that Cdk6-D3 may play a central role controlling cell's proliferation
competence (47). Consistently,
a few fold overexpression of Cdk6-D3 elevates by up to 106
folds the susceptibility of rodent fibroblasts to UV irradiation-
or 3-methylcholanthrene-induced malignant transformation (51).
We are currently scrutinizing this possibility. |
