11840272

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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.

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0887-6924

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127-34

pubmed-meshheading:11840272-Apoptosis, pubmed-meshheading:11840272-Cell Cycle, pubmed-meshheading:11840272-Cell Cycle Proteins, pubmed-meshheading:11840272-Cell Division, pubmed-meshheading:11840272-Cyclin D1, pubmed-meshheading:11840272-Cyclin-Dependent Kinase 6, pubmed-meshheading:11840272-Cyclin-Dependent Kinase Inhibitor p18, pubmed-meshheading:11840272-Cyclin-Dependent Kinases, pubmed-meshheading:11840272-Enzyme Inhibitors, pubmed-meshheading:11840272-Gene Deletion, pubmed-meshheading:11840272-Genes, Tumor Suppressor, pubmed-meshheading:11840272-Genotype, pubmed-meshheading:11840272-Humans, pubmed-meshheading:11840272-Lymphoma, Mantle-Cell, pubmed-meshheading:11840272-Multiple Myeloma, pubmed-meshheading:11840272-Neoplasm Proteins, pubmed-meshheading:11840272-Protein-Serine-Threonine Kinases, pubmed-meshheading:11840272-Recombinant Fusion Proteins, pubmed-meshheading:11840272-Transfection, pubmed-meshheading:11840272-Tumor Cells, Cultured, pubmed-meshheading:11840272-Tumor Suppressor Proteins

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.

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