Opposing regulation of choline deficiency-induced apoptosis by p53 and nuclear factor kappa B.

Citation
Mq. Holmes-mcnary et al., Opposing regulation of choline deficiency-induced apoptosis by p53 and nuclear factor kappa B., J BIOL CHEM, 276(44), 2001, pp. 41197-41204
Citations number
69
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
44
Year of publication
2001
Pages
41197 - 41204
Database
ISI
SICI code
0021-9258(20011102)276:44<41197:OROCDA>2.0.ZU;2-R
Abstract
We have previously shown that fetal rat brain cells, preneuronal (PC12), an d hepatocyte (CWSV-1) cells undergo apoptosis during choline deficiency (CD ). The PC12 and epithelial cell culture models were used to determine the m olecular mechanism by which CD induces apoptosis. Our data indicate that CD leads to both growth arrest and apoptosis in a subpopulation of cells, whi ch correlate with the up-regulation of the tumor suppressor protein p53 and concurrent up-regulation of the cyclin-dependent kinase-inhibitor p21(WAF1 /CIP1). Additionally, CD induced both a G(1)/S and a G(2)/M arrest. Transie nt transfection of a dominant negative p53 (p53DN) construct. into PC12 cel ls, which inhibited endogenous p53 activation, significantly reduced the in duction of apoptosis associated with CD. Interestingly, CD also induced the persistent activation of the transcription factor NF-B. Activation of NF-K B has been shown to promote cell survival and proposed to antagonize p53. C onsistent with this, expression of a super-repressor form of l kappaB alpha (SR-I kappaB alpha) that functions to strongly inhibit NF-KB activation, p rofoundly enhanced cell death during CD. In summary, these results suggest that the effects of CD on apoptosis and subsequent cell survival are mediat ed through two different signaling pathways, p53 and NF-kappaB, respectivel y. Taken together, our data demonstrates the induction of opposing mechanis ms associated with nutrient deficiency that may provide a molecular mechani sm by which CD promotes carcinogenesis.