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

M. S. Kulkarni, J. L. Daggett, T. P. Bender, W. M. Kuehl, Peter Leif Bergsagel, M. E. Williams

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)127-134
Number of pages8
JournalLeukemia
Volume16
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase Inhibitor p18
Cyclin D1
Multiple Myeloma
Apoptosis
Cell Line
Growth
Cyclin-Dependent Kinase Inhibitor p15
Plasma Cell Neoplasms
Neoplasms
Trypan Blue
Tumor Cell Line
Zinc
Cell Cycle
Carcinogenesis
Cell Death
Ectopic Gene Expression
Genes

Keywords

  • Apoptosis
  • Cell cycle
  • Cyclin D1
  • Mantle cell lymphoma
  • Multiple myeloma
  • p18

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

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. / Kulkarni, M. S.; Daggett, J. L.; Bender, T. P.; Kuehl, W. M.; Bergsagel, Peter Leif; Williams, M. E.

In: Leukemia, Vol. 16, No. 1, 2002, p. 127-134.

Research output: Contribution to journalArticle

@article{919ff17bb30144cf86b3571009a47f65,
title = "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",
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.",
keywords = "Apoptosis, Cell cycle, Cyclin D1, Mantle cell lymphoma, Multiple myeloma, p18",
author = "Kulkarni, {M. S.} and Daggett, {J. L.} and Bender, {T. P.} and Kuehl, {W. M.} and Bergsagel, {Peter Leif} and Williams, {M. E.}",
year = "2002",
doi = "10.1038/sj/leu/2402328",
language = "English (US)",
volume = "16",
pages = "127--134",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines

T2 - Ectopic p18 expression inhibits growth and induces apoptosis

AU - Kulkarni, M. S.

AU - Daggett, J. L.

AU - Bender, T. P.

AU - Kuehl, W. M.

AU - Bergsagel, Peter Leif

AU - Williams, M. E.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cell cycle

KW - Cyclin D1

KW - Mantle cell lymphoma

KW - Multiple myeloma

KW - p18

UR - http://www.scopus.com/inward/record.url?scp=85009921564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009921564&partnerID=8YFLogxK

U2 - 10.1038/sj/leu/2402328

DO - 10.1038/sj/leu/2402328

M3 - Article

VL - 16

SP - 127

EP - 134

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 1

ER -