Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis

Leukemia. 2002 Jan;16(1):127-34. doi: 10.1038/sj.leu.2402328.

Abstract

Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20-25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.

Publication types

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

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Cell Cycle
  • Cell Cycle Proteins*
  • Cell Division
  • Cyclin D1 / physiology
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinases*
  • Enzyme Inhibitors
  • Gene Deletion*
  • Genes, Tumor Suppressor*
  • Genotype
  • Humans
  • Lymphoma, Mantle-Cell / pathology
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / physiology
  • Protein-Serine-Threonine Kinases / physiology
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / physiology

Substances

  • CDKN2C protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p18
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Protein-Serine-Threonine Kinases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases