Enforced expression of the tumor suppressor p53 renders human leukemia cells (U937) more sensitive to 1-[beta-D-arabinofuranosyl]cytosine (ara-C)-induced apoptosis

Biochemical Pharmacology
Roy H DeckerSteven Grant

Abstract

The effects of enforced expression of p53 on the sensitivity of p53(-/-) human monocytic leukemia cells (U937) to apoptosis following exposure to the S-phase-specific antimetabolite 1-[beta-D-arabinofuranosyl]cytosine (ara-C) were examined. Cells were stably transfected with a plasmid containing a chimeric DNA construct encoding a temperature-sensitive p53 variant (135(ala-->val)), which transactivates at 32 degrees but is non-functional at 37 degrees. A significant reduction in the S-phase population was observed in ptsp53 mutants incubated at 32 degrees. Nevertheless, while vector controls did not exhibit differential sensitivity to ara-C at 32 degrees versus 37 degrees, temperature-sensitive p53 mutants displayed a significant increase in apoptosis at the permissive temperature. This was not accompanied by increased ara-CTP formation, DNA incorporation of [3H]ara-C, or altered expression of Bcl-2 or Bax. Enhanced sensitivity was associated with increased mitochondrial injury (e.g. cytochrome c release), caspase activation, and loss of clonogenic survival. Significantly, ptsp53 cells synchronized in S phase were markedly more sensitive to ara-C-mediated mitochondrial injury and apoptosis at 32 degrees, indicating that wild-ty...Continue Reading

References

May 15, 1976·International Journal of Cancer. Journal International Du Cancer·C Sundström, K Nilsson
Mar 1, 1992·The American Journal of Medicine·D M MastrianniD G Tenen
Jun 21, 1991·Science·S E KernB Vogelstein
Oct 6, 1995·Science·C M KnudsonS J Korsmeyer
Dec 1, 1994·Molecular and Cellular Biology·B Shan, W H Lee
Nov 19, 1993·Cell·W S el-DeiryB Vogelstein
Dec 1, 1995·Molecular and Cellular Biology·S W HiebertJ L Cleveland
Jan 23, 1996·Proceedings of the National Academy of Sciences of the United States of America·B ShanW H Lee
Jun 7, 1996·Biochimica Et Biophysica Acta·T M Gottlieb, M Oren
Aug 1, 1996·Genes & Development·K PolyakB Vogelstein
Mar 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·M E McCurrachS W Lowe
Sep 26, 1997·Nature·K PolyakB Vogelstein
May 13, 1999·Proceedings of the National Academy of Sciences of the United States of America·S KrajewskiJ C Reed
Aug 3, 1999·The Journal of Clinical Investigation·F BunzB Vogelstein
Feb 28, 2002·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Kalpana BallalPeng Huang
Jun 27, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Liang QiaoPaul Dent

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