Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest.
Iron plays an essential role in cell proliferation and is a required cofactor for a number of critical cellular enzymes. In this report we investigate changes in proteins of iron metabolism during p53-mediated replicative arrest. Following the induction of p53 in H1299 lung cancer cells containing a doxycycline-inducible p53, an increase in both H and L subunits of ferritin protein was observed. To determine the mechanism of this effect, we investigated the ability of p53 to regulate ferritin. Real time reverse transcription-PCR demonstrated no difference in levels of ferritin H mRNA in the presence and absence of p53. Because these results suggested that transcriptional mechanisms were not responsible for the p53-dependent increase in ferritin, we tested whether a post-transcriptional mechanism was involved. RNA bandshift assays revealed that induction of p53 decreased iron regulatory protein binding. Consistent with this observation, Western blot analysis revealed a decline in transferrin receptor 1 protein levels following induction of p53. Collectively, these results suggest that p53 may induce cell cycle arrest not only by well described mechanisms involving the induction of cyclin-dependent kinase inhibitors but also by the recruitment of pathways that reduce the availability of intracellular iron.
Zhang
Fan
F
Department of Cancer Biology, Wake Forest University, Winston-Salem, NC 27157, USA.
Wang
Wei
W
Tsuji
Yoshiaki
Y
Torti
Suzy V
SV
Torti
Frank M
FM
D015703:Antigens, CD / Q000737:chemistry; D001052:Apoferritins / Q000737:chemistry; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000737:chemistry; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005293:Ferritins / Q000737:chemistry; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000737:chemistry*; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012323:RNA Processing, Post-Transcriptional; D011990:Receptors, Transferrin / Q000737:chemistry; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000098742:Ferroportin
D015703:Antigens, CD; C068126:CD71 antigen; D027682:Cation Transport Proteins; D011990:Receptors, Transferrin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000098742:Ferroportin; D005293:Ferritins; D001052:Apoferritins; D007501:Iron