Stabilization of p53 is a novel mechanism for proapoptotic function of NF-kappaB.

Published

Journal Article

Both pro- and antiapoptotic activities of NF-kappaB transcription factor have been observed; however, less is known about the mechanism by which NF-kappaB induces apoptosis. To elucidate how NF-kappaB regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1(-/-), ikk2(-/-), rela(-/-) murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IkappaBalphaM, and HCT116/p53(+/+) and HCT116/p53(-/-) cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-kappaB, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-kappaB-dependent p53 activity induced the expression of p53-regulated genes PUMA and p21(waf1) as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IkappaBalpha (IkappaBalphaM) inhibited NF-kappaB-dependent p53 activation and apoptosis. The doxycycline-induced NF-kappaB activation was not inhibited in HCT116/p53(-/-) cells. Our results demonstrate that NF-kappaB plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-kappaB-regulated proapoptotic signaling.

Full Text

Duke Authors

Cited Authors

  • Fujioka, S; Schmidt, C; Sclabas, GM; Li, Z; Pelicano, H; Peng, B; Yao, A; Niu, J; Zhang, W; Evans, DB; Abbruzzese, JL; Huang, P; Chiao, PJ

Published Date

  • June 25, 2004

Published In

Volume / Issue

  • 279 / 26

Start / End Page

  • 27549 - 27559

PubMed ID

  • 15102862

Pubmed Central ID

  • 15102862

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M313435200

Language

  • eng

Conference Location

  • United States