Apoptotic Signaling Pathways Induced by Nitric Oxide in Human Lymphoblastoid Cells Expressing Wild-Type or Mutant p53

Chun Qi Li, Ana I. Robles, Christin L. Hanigan, Lorne J. Hofseth, Laura J. Trudel, Curtis C. Harris, Gerald N. Wogan

Research output: Contribution to journalArticle

Abstract

Loss of p53 function by inactivating mutations results in abrogation of NO.-induced apoptosis in human lymphoblastoid cells. Here we report characterization of apoptotic signaling pathways activated by NO. in these cells by cDNA microarray expression and immunoblotting. A p53-mediated transcriptional response to NO. was observed in p53-wild-type TK6, but not in closely related p53-mutant WTK1, cells. Several previously characterized p53 target genes were up-regulated transcriptionally in TK6 cells, including phosphatase PPM1D (WIP1), oxidoreductase homolog PIG3, death receptor TNFRSF6 (Fas/CD95), and BH3-ouly proteins BBC3 (PUMA) and PMAIP1 (NOXA). NO. also modulated levels of several gene products in the mitochondria-dependent and death-receptor-mediated apoptotic pathways. Inhibitors of apoptosis proteins X-chromosome-linked inhibitor of apoptosis, cellular inhibitor of apoptosis protein-1, and survivin were significantly down-regulated in TK6 cells, but not in WTK1 cells. Smac release from mitochondria was induced in both cell types, but release of apoptosis-inducing factor and endonuclease G was detected only in TK6 cells. Fas/CD95 was increased, and levels of the antiapoptotic proteins Bcl-2 and Bcl-x/L were reduced in TK6 cells. Activation of procaspases 3, 8, 9, and 10, as well as Bid and poly(ADP-ribose) polymerase cleavage, were observed only in TK6 cells. No. treatment did not alter levels of death receptors 4 and 5, Fas-associated death domain or proapoptotic Bax and Bak proteins in either cell line. Collectively, these data show that NO. exposure activated a complex network of responses leading to p53-dependent apoptosis via both mitochondrial and Fas receptor pathways, which were abrogated in the presence of mutant p53.

Original languageEnglish (US)
Pages (from-to)3022-3029
Number of pages8
JournalCancer Research
Volume64
Issue number9
DOIs
StatePublished - May 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Li, C. Q., Robles, A. I., Hanigan, C. L., Hofseth, L. J., Trudel, L. J., Harris, C. C., & Wogan, G. N. (2004). Apoptotic Signaling Pathways Induced by Nitric Oxide in Human Lymphoblastoid Cells Expressing Wild-Type or Mutant p53. Cancer Research, 64(9), 3022-3029. https://doi.org/10.1158/0008-5472.CAN-03-1880