L. Fromm et Pa. Overbeek, REGULATION OF CYCLIN AND CYCLIN-DEPENDENT KINASE GENE-EXPRESSION DURING LENS DIFFERENTIATION REQUIRES THE RETINOBLASTOMA PROTEIN, Oncogene, 12(1), 1996, pp. 69-75
The retinoblastoma protein (pRb) functions as a negative regulator of
the cell cycle and is essential to maintain certain cell types in a po
st-mitotic state during terminal differentiation. In the ocular lens,
inactivation of this protein is sufficient to cause lens fiber cells,
which are normally post-mitotic, to enter the cell cycle. The current
studies address whether regulation of the cell cycle during lens fiber
differentiation in normal lenses or in lenses in which pRB has been i
nactivated is accompanied by changes in expression of cyclin and cycli
n-dependent kinase genes. In the normal lens, our experiments using in
-situ hybridization reveal that the expression of cyclin A, cyclin B1,
cdc2 and cdk2 is restricted to the proliferative epithelial cells, wi
th no expression in the differentiating fiber cells. Cyclins D1 and D2
and cdk4 show a less restrictive pattern and are expressed in some of
the post-mitotic cells. Lenses from RB-deficient embryos, in contrast
, show inappropriate expression in the fiber cells of cyclins A, B1 an
d E, as well as cdc2 and cdk2. The lens fiber cells in these embryos e
xpress protein markers for differentiation, such as beta- and gamma-cr
ystallins, even though the cells do not withdraw from the cell cycle.
These results indicate that the regulated expression of multiple cell
cycle regulatory genes during lens fiber cell differentiation requires
the presence of pRb.