I. Matushansky et al., Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G(1), P NAS US, 97(26), 2000, pp. 14317-14322
Citations number
47
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Some tumor cells can be stimulated to differentiate and undergo terminal ce
ll division and loss of tumorigenicity. The in vitro differentiation of mur
ine erythroleukemia (MEL) cells is a dramatic example of tumor-cell reprogr
amming. We found that reentry of MEL cells into terminal differentiation is
accompanied by an early transient decline in the activity of cyclin-depend
ant kinase (CDK) 2, followed by a decline of CDK6. Later, as cells undergo
terminal arrest, CDK2 and CDK4 activities decline. By analyzing stable MEL-
cell transfectants containing vectors directing inducible expression of spe
cific CDK inhibitors, we show that only inhibitors that block the combinati
on of CDK2 and CDK6 trigger differentiation. Inhibiting CDK2 and CDK4 does
not cause differentiation. Importantly. we also show that reprogramming thr
ough inhibition of CDKs is restricted to G(1) phase of the cell cycle. The
results imply that abrogation of normal cell-cycle controls in tumor cells
contributes to their inability to differentiate fully and that restoration
of such controls in G(1) can lead to resumption of differentiation and term
inal cell division. The results also indicate that CDK4 and CDK6 are functi
onally distinct and support our hypothesis that the two CDKs regulate cell
division at different stages of erythroid maturation.