LOVASTATIN MEDIATED G1 ARREST IN NORMAL AND TUMOR BREAST CELLS IS THROUGH INHIBITION OF CDK2 ACTIVITY AND REDISTRIBUTION OF P21 AND P27, INDEPENDENT OF P53
S. Rao et al., LOVASTATIN MEDIATED G1 ARREST IN NORMAL AND TUMOR BREAST CELLS IS THROUGH INHIBITION OF CDK2 ACTIVITY AND REDISTRIBUTION OF P21 AND P27, INDEPENDENT OF P53, Oncogene, 17(18), 1998, pp. 2393-2402
Previously, we reported that lovastatin, a potent inhibitor of the enz
yme HMG CoA reductase also acts as an antimitogenic agent by arresting
cells in the G1 phase of the cell cycle resulting in cell cycle-indep
endent alteration of cyclin dependent kinase inhibitors (CKIs), In the
present study we have investigated the nature of the CKIs (p21 and p2
7) alterations resulting in G1 arrest in both normal and tumor breast
cell lines by lovastatin, We show that even though lovastatin treatmen
t causes G1 arrest in a wide variety of normal and tumor breast cells
irrespective of their p53 or pRb status, the p21 and p27 protein level
s are not increased in all cell lines treated suggesting that the incr
ease in p21 and p27 protein expression per se is not necessary for lov
astatin mediated G1 arrest. However, the binding of p21 and p27 to CDK
2 increases significantly following treatment of cells with lovastatin
leading to inhibition of CDK2 activity and a subsequent arrest of cel
ls in G1, The increased CKI binding to CDK2 is achieved by the redistr
ibution of both p21 and p27 from CDK4 to CDK2 complexes subsequent to
decreases in CDK4 and cyclin D3 expression following lovastatin treatm
ent, Lastly, we show that lovastatin treatment of 76N-E6 breast cell l
ine with an altered p53 pathway also results in G1 arrest and similar
redistribution of CKIs from CDK4 to CDK2 as observed in other breast c
ell lines examined, These observations suggest that lovastatin induced
G1 arrest of breast cell lines is through a p53 independent pathway a
nd is mediated by decreased CDK2 activity through redistribution of CK
Is from CDK4 to CDK2.