3 induced apoptosis in mcl lines at 2 4 u03bcm which is within the plasma levels achieved after as 2 o 3 therapy as 2 o 3 induces a dose and time dependent suppression of cyclin d1 the suppression of cyclin d1 restores rb to a hypophosphorylated state in parallel with a change in cell cycle these biologic changes are consistent with the apoptosis observed upon as 2 o 3 treatment the down regulation of cyclin d1 mediated by as 2 o 3 occurs at a post transcriptional level since cyclin d1 is under the transcriptional control of the immunoglobulin heavy chain gene enhancer in mcl which is unlikely to be affected by as 2 o 3 furthermore in physiologic conditions the control of cyclin d1 during the cell cycle is also mediated in part via alteration in the stability of cyclin d1 this process is controlled by phosphorylation of cyclin d1 at thr 286 a process mediated by gsk 3 u03b2 gsk 3 u03b2 is itself tightly regulated mitogens inactivate gsk 3 u03b2 by a pathway involving ras phosphatidylinositol 3 kinase pi3k and protein kinaseb akt ras activates pi3k which in turn activates akt akt inactivates gsk 3 u03b2 by phosphorylating it at serine residue.