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Suppression of c-myc expression and c-myc function in response to sustained DNA damage in mcf-7 breast tumor cells

Academic Article
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Overview

authors

  • Magnet, K. J.
  • Orr, M. S.
  • Cleveland, John
  • Rodriguez-Galindo, C.
  • Yang, H.
  • Yang, C. Y.
  • Di, Y. M.
  • Jain, P. T.
  • Gewirtz, D. A.

publication date

  • September 2001

journal

  • Biochemical Pharmacology  Journal

abstract

  • The topoisomerase II inhibitors teniposide (VM-26), doxorubicin, and amsacrine (m-AMSA), as well as ionizing radiation, induce a transient suppression of c-myc mRNA, which correlates with growth inhibition of MCF-7 breast tumor cells. To further assess the involvement of c-mvc in the DNA damage-induced signal transduction pathways of the breast tumor cell, we determined the influence of sustained DNA damage on c-myc expression, c-Myc protein levels and c-Myc function. Continuous exposure of MCF-7 breast tumor cells to VM-26 induced DNA strand breaks that were sustained for at least 9 hr. DNA strand breakage was accompanied by a decline in c-myc transcripts and c-Myc protein levels by >90% after VM-26 exposure for 24 hr. The activity of a transcriptional target of the c-Myc protein, ornithine decarboxylase, was reduced by approximately 75% within 9 hr of DNA damage, in parallel to the declines in c-myc mRNA and protein levels. Extended exposure to VM-26 resulted in an initial loss of approximately 35% of the cell population followed by the death of additional cells such that by 72 hr only 50% of the cells were viable. Although apoptosis was evident 72 hr after initiating drug exposure [based on cell cycle analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and an assessment of cell morphology], the primary phase of cell killing, which occurred during the first 24 hr was non-apoptotic. These studies indicate that non-apoptotic pathways can also mediate cell death in the breast tumor cell and support the role of c-myc expression, c-Myc protein, and c-Myc function as elements of the DNA damage response pathway in the breast tumor cell.

subject areas

  • Antineoplastic Agents
  • Apoptosis
  • Breast Neoplasms
  • Cell Cycle
  • Cell Death
  • DNA Damage
  • G1 Phase
  • Gene Expression
  • Gene Silencing
  • Humans
  • Ornithine Decarboxylase
  • Ornithine Decarboxylase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Teniposide
  • Transcription, Genetic
  • Tumor Cells, Cultured
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Research

keywords

  • DNA damage
  • MCF-7
  • VM-26 (teniposide)
  • c-Myc
  • ornithine decarboxylase
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Identity

International Standard Serial Number (ISSN)

  • 0006-2952

Digital Object Identifier (DOI)

  • 10.1016/s0006-2952(01)00699-2

PubMed ID

  • 11585056
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Additional Document Info

start page

  • 593

end page

  • 602

volume

  • 62

issue

  • 5

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