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.
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Authors | M S Kulkarni, J L Daggett, T P Bender, W M Kuehl, P L Bergsagel, M E Williams |
Journal | Leukemia
(Leukemia)
Vol. 16
Issue 1
Pg. 127-34
(Jan 2002)
ISSN: 0887-6924 [Print] England |
PMID | 11840272
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- 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
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Topics |
- Apoptosis
(genetics, 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, pathology)
- Neoplasm Proteins
(genetics, physiology)
- Protein Serine-Threonine Kinases
(physiology)
- Recombinant Fusion Proteins
(physiology)
- Transfection
- Tumor Cells, Cultured
- Tumor Suppressor Proteins
(genetics, physiology)
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