Constitutive expression of ectopic c-Myc delays glucocorticoid-evoked apoptosis of human leukemic CEM-C7 cells

Oncogene. 2001 Aug 2;20(34):4629-39. doi: 10.1038/sj.onc.1204680.

Abstract

Sensitivity to glucocorticoid (GC)-evoked apoptosis in lymphoid cell lines correlates closely with GC-mediated suppression of c-Myc expression. To establish a functional role for c-Myc in GC-mediated apoptosis, we have stably expressed MycER(TM), the human c-Myc protein fused to the modified ligand-binding domain of the murine estrogen receptor alpha, in GC-sensitive CEM-C7-14 cells. In CEM-C7-14 cells, MycER(TM) constitutively imparts c-Myc functions. Cells expressing MycER(TM) (C7-MycER(TM)) exhibited a marked reduction in cell death after 72 h in 100 nM dexamethasone (Dex), with 10-20-fold more viable cells when compared to the parental CEM-C7-14 clone. General GC responsiveness was not compromised, as evidenced by Dex-mediated suppression of endogenous c-Myc and cyclin D3, and induction of c-Jun and the glucocorticoid receptor. MycER(TM) also blunted Dex-mediated upregulation of p27(kipI) and suppression of the Myc target p53. In comparison to parental CEM-C7-14 cells, Dex-evoked DNA strand breaks were negligible and caspase activation was delayed, but the extent of G1 cell cycle arrest was similar in C7-MycER(TM) cells. Myc-ER(TM) did not result in permanent, complete resistance to GC however, and the GC-treated cells eventually died, indicative of redundant or interactive mechanisms in the GC-evoked lytic response of lymphoid cells. Our results emphasize the importance of c-Myc suppression in GC-evoked apoptosis of CEM-C7-14 cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Apoptosis*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic-Leucine Zipper Transcription Factors
  • Biopterins / analogs & derivatives*
  • Biopterins / pharmacology
  • Caspase 3
  • Caspases / metabolism
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Clone Cells
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA Damage
  • DNA-Binding Proteins / metabolism
  • Dexamethasone / pharmacology*
  • Estrogen Receptor alpha
  • G1 Phase / drug effects
  • Glucocorticoids / pharmacology*
  • Humans
  • Leukemia, Lymphoid / metabolism
  • Leukemia, Lymphoid / pathology*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Proto-Oncogene Proteins c-myc / physiology*
  • Receptors, Estrogen / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transcription Factors*
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*

Substances

  • Antineoplastic Agents, Hormonal
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic-Leucine Zipper Transcription Factors
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Estrogen Receptor alpha
  • Glucocorticoids
  • MAX protein, human
  • Myc associated factor X
  • Proto-Oncogene Proteins c-myc
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Biopterins
  • Dexamethasone
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • sapropterin