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. 1998 Nov 5;17(18):2393-402. doi: 10.1038/sj.onc.1202322.


Previously, we reported that lovastatin, a potent inhibitor of the enzyme HMG CoA reductase also acts as an antimitogenic agent by arresting cells in the G1 phase of the cell cycle resulting in cell cycle-independent alteration of cyclin dependent kinase inhibitors (CKIs). In the present study we have investigated the nature of the CKIs (p21 and p27) alterations resulting in G1 arrest in both normal and tumor breast cell lines by lovastatin. We show that even though lovastatin treatment 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 levels are not increased in all cell lines treated suggesting that the increase in p21 and p27 protein expression per se is not necessary for lovastatin mediated G1 arrest. However, the binding of p21 and p27 to CDK2 increases significantly following treatment of cells with lovastatin leading to inhibition of CDK2 activity and a subsequent arrest of cells in G1. The increased CKI binding to CDK2 is achieved by the redistribution of both p21 and p27 from CDK4 to CDK2 complexes subsequent to decreases in CDK4 and cyclin D3 expression following lovastatin treatment. Lastly, we show that lovastatin treatment of 76N-E6 breast cell line with an altered p53 pathway also results in G1 arrest and similar redistribution of CKIs from CDK4 to CDK2 as observed in other breast cell lines examined. These observations suggest that lovastatin induced G1 arrest of breast cell lines is through a p53 independent pathway and is mediated by decreased CDK2 activity through redistribution of CKIs from CDK4 to CDK2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Breast / metabolism
  • Breast Neoplasms / metabolism
  • CDC2-CDC28 Kinases*
  • Cell Cycle Proteins*
  • Cyclin D3
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / metabolism*
  • Female
  • G1 Phase / drug effects*
  • Humans
  • Lovastatin / pharmacology*
  • Microtubule-Associated Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins*
  • Retinoblastoma Protein / metabolism
  • Tumor Cells, Cultured / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins*


  • Antineoplastic Agents
  • CCND3 protein, human
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin D3
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Lovastatin
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases