Opposing regulation of choline deficiency-induced apoptosis by p53 and nuclear factor kappaB.
We have previously shown that fetal rat brain cells, preneuronal (PC12), and hepatocyte (CWSV-1) cells undergo apoptosis during choline deficiency (CD). The PC12 and epithelial cell culture models were used to determine the molecular mechanism by which CD induces apoptosis. Our data indicate that CD leads to both growth arrest and apoptosis in a subpopulation of cells, which 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 G1/S and a G2/M arrest. Transient transfection of a dominant negative p53 (p53DN) construct into PC12 cells, which inhibited endogenous p53 activation, significantly reduced the induction of apoptosis associated with CD. Interestingly, CD also induced the persistent activation of the transcription factor NF-kappaB. Activation of NF-kappaB has been shown to promote cell survival and proposed to antagonize p53. Consistent with this, expression of a super-repressor form of IkappaBalpha (SR-IkappaBalpha) that functions to strongly inhibit NF-kappaB activation, profoundly enhanced cell death during CD. In summary, these results suggest that the effects of CD on apoptosis and subsequent cell survival are mediated through two different signaling pathways, p53 and NF-kappaB, respectively. Taken together, our data demonstrates the induction of opposing mechanisms associated with nutrient deficiency that may provide a molecular mechanism by which CD promotes carcinogenesis.
Holmes-McNary
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MQ
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA. holmes-mcnary.1@osu.edu
Baldwin
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AS
Zeisel
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SH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival; D002796:Choline Deficiency / Q000150:complications*; D024202:Electrophoretic Mobility Shift Assay; D020287:In Situ Nick-End Labeling; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53