DOI: 10.1073/pnas.96.7.3940. Transient excess of <i>MYC</i> activity can elicit genomic instability and tumorigenesis

Transient excess of MYC activity can elicit genomic instability and tumorigenesis

10.1073/pnas.96.7.3940

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Overexpression of the MYC protooncogene has been implicated in the genesis of diverse human tumors. Tumorigenesis induced by MYC has been attributed to sustained effects on proliferation and differentiation. Here we report that MYC may also contribute to tumorigenesis by destabilizing the cellular genome. A transient excess of MYC activity increased tumorigenicity of Rat1A cells by at least 50-fold. The increase persisted for >30 days after the return of MYC activity to normal levels. The brief surfeit of MYC activity was accompanied by evidence of genomic instability, including karyotypic abnormalities, gene amplification, and hypersensitivity to DNA-damaging agents. MYC also induced genomic destabilization in normal human fibroblasts, although these cells did not become tumorigenic. Stimulation of Rat1A cells with MYC accelerated their passage through G 1 /S. Moreover, MYC could force normal human fibroblasts to transit G 1 and S after treatment with N- (phosphonoacetyl)- l -aspartate (PALA) at concentrations that normally lead to arrest in S phase by checkpoint mechanisms. Instead, the cells subsequently appeared to arrest in G 2 . We suggest that the accelerated passage through G 1 was mutagenic but that the effect of MYC permitted a checkpoint response only after G 2 had been reached. Thus, MYC may contribute to tumorigenesis through a dominant mutator effect.

Bibliography

Felsher, D. W., & Bishop, J. M. (1999). Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proceedings of the National Academy of Sciences, 96(7), 3940â3944.

Authors 2

Dean W. Felsher (first)
J. Michael Bishop (additional)

References 30 Referenced 333

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:35 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:41 p.m.)
Indexed	1 month, 4 weeks ago (July 1, 2025, 9:30 a.m.)
Issued	26 years, 5 months ago (March 30, 1999)
Published	26 years, 5 months ago (March 30, 1999)
Published Online	26 years, 5 months ago (March 30, 1999)
Published Print	26 years, 5 months ago (March 30, 1999)

Funders 0

None

BibTeX

@article{Felsher_1999, title={Transient excess of MYC activity can elicit genomic instability and tumorigenesis}, volume={96}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.96.7.3940}, DOI={10.1073/pnas.96.7.3940}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Felsher, Dean W. and Bishop, J. Michael}, year={1999}, month=mar, pages={3940–3944} }

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  "abstract": "<jats:p>\n            Overexpression of the\n            <jats:italic>MYC</jats:italic>\n            protooncogene has been implicated in the genesis of diverse human tumors. Tumorigenesis induced by\n            <jats:italic>MYC</jats:italic>\n            has been attributed to sustained effects on proliferation and differentiation. Here we report that\n            <jats:italic>MYC</jats:italic>\n            may also contribute to tumorigenesis by destabilizing the cellular genome. A transient excess of\n            <jats:italic>MYC</jats:italic>\n            activity increased tumorigenicity of Rat1A cells by at least 50-fold. The increase persisted for &gt;30 days after the return of\n            <jats:italic>MYC</jats:italic>\n            activity to normal levels. The brief surfeit of\n            <jats:italic>MYC</jats:italic>\n            activity was accompanied by evidence of genomic instability, including karyotypic abnormalities, gene amplification, and hypersensitivity to DNA-damaging agents.\n            <jats:italic>MYC</jats:italic>\n            also induced genomic destabilization in normal human fibroblasts, although these cells did not become tumorigenic. Stimulation of Rat1A cells with\n            <jats:italic>MYC</jats:italic>\n            accelerated their passage through G\n            <jats:sub>1</jats:sub>\n            /S. Moreover,\n            <jats:italic>MYC</jats:italic>\n            could force normal human fibroblasts to transit G\n            <jats:sub>1</jats:sub>\n            and S after treatment with\n            <jats:italic>N-</jats:italic>\n            (phosphonoacetyl)-\n            <jats:sc>l</jats:sc>\n            -aspartate (PALA) at concentrations that normally lead to arrest in S phase by checkpoint mechanisms. Instead, the cells subsequently appeared to arrest in G\n            <jats:sub>2</jats:sub>\n            . We suggest that the accelerated passage through G\n            <jats:sub>1</jats:sub>\n            was mutagenic but that the effect of\n            <jats:italic>MYC</jats:italic>\n            permitted a checkpoint response only after G\n            <jats:sub>2</jats:sub>\n            had been reached. Thus,\n            <jats:italic>MYC</jats:italic>\n            may contribute to tumorigenesis through a dominant mutator effect.\n          </jats:p>",
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