Multiple mechanisms of N-phosphonacetyl-L-aspartate resistance in human cell lines: Carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged

K. A. Smith, O. B. Chernova, R. P. Groves, M. B. Stark, J. L. Martinez, J. N. Davidson, J. M. Trent, T. E. Patterson, A. Agarwal, P. Duncan, M. L. Agarwal, G. R. Stark

Research output: Contribution to journalArticle

Abstract

Rodent cells resistant to N-phosphonacetyl-L-aspartate (PALA) invariably contain amplified carbamyl-P synthetase/aspartate transcarbamylase/dihydro- orotase (CAD) genes, usually in widely spaced tandem arrays present as extensions of the same chromosome arm that carries a single copy of CAD in normal cells. In contrast, amplification of CAD is very infrequent in several human tumor cell lines. Cell lines with minimal chromosomal rearrangement and with unrearranged copies of chromosome 2 rarely develop intrachromosomal amplifications of CAD. These cells frequently become resistant to PALA through a mechanism that increases the aspartate transcarbamylase activity with no increase in CAD copy number, or they obtain one extra copy of CAD by forming an isochromosome 2p or by retaining an extra copy of chromosome 2. In cells with multiple chromosomal aberrations and rearranged copies of chromosome 2, amplification of CAD as tandem arrays from rearranged chromosomes is the most frequent mechanism of PALA resistance. All of these different mechanisms of PALA resistance are blocked in normal human fibroblasts.

Original languageEnglish (US)
Pages (from-to)1816-1821
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number5
DOIs
StatePublished - 1997
Externally publishedYes

Fingerprint

NSC 224131
Dihydroorotase
Aspartate Carbamoyltransferase
Chromosomes, Human, Pair 2
Gene Amplification
Ligases
Aspartic Acid
Cell Line
Chromosomes
Isochromosomes
Tumor Cell Line
Chromosome Aberrations
Rodentia
Fibroblasts
Genes

Keywords

  • chromosome rearrangements
  • fluorescence in situ hybridization
  • genomic stability
  • induced amplication
  • isochromosome 2

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Multiple mechanisms of N-phosphonacetyl-L-aspartate resistance in human cell lines : Carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged. / Smith, K. A.; Chernova, O. B.; Groves, R. P.; Stark, M. B.; Martinez, J. L.; Davidson, J. N.; Trent, J. M.; Patterson, T. E.; Agarwal, A.; Duncan, P.; Agarwal, M. L.; Stark, G. R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 5, 1997, p. 1816-1821.

Research output: Contribution to journalArticle

Smith, K. A. ; Chernova, O. B. ; Groves, R. P. ; Stark, M. B. ; Martinez, J. L. ; Davidson, J. N. ; Trent, J. M. ; Patterson, T. E. ; Agarwal, A. ; Duncan, P. ; Agarwal, M. L. ; Stark, G. R. / Multiple mechanisms of N-phosphonacetyl-L-aspartate resistance in human cell lines : Carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 5. pp. 1816-1821.
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AU - Smith, K. A.

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AU - Agarwal, M. L.

AU - Stark, G. R.

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