Zinc binding and redox control of p53 structure and function.
The p53 protein is a tumor suppressor often inactivated in cancer, which controls cell proliferation and survival through several coordinated pathways. The p53 protein is induced in response to many forms of cellular stress, genotoxic or not. p53 is a zinc-binding protein containing several reactive cysteines, and its key biochemical property, sequence-specific DNA binding, is dependent upon metal and redox regulation in vitro. In this review, we describe the main features of p53 as a metalloprotein and we discuss how metal binding and oxidation-reduction may affect p53 activity in vivo. In particular, we stress the possible involvement of thioredoxin, Ref-1 (redox factor 1), and metallothionein in the control of p53 protein conformation and activity. Furthermore, we also review the available evidence on the role of p53 as a transactivator or transrepressor of genes involved in the production and control of reactive oxygen intermediates. Overall, these data indicate that p53 lies at the center of a network of complex redox interactions. In this network, p53 can control the timely production of reactive oxygen intermediates (e.g., to initiate apoptosis), but this activity is itself under the control of changes in metal levels and in cellular redox status. This redox sensitivity may be one of the biochemical mechanisms by which p53 acts as a "sensor" of multiple forms of stress.
Hainaut
P
P
Group of Molecular Carcinogenesis, International Agency for Research on Cancer, Lyon, France. Hainaut@iarc.fr
Mann
K
K
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D019757:Carbon-Oxygen Lyases / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D005786:Gene Expression Regulation; D006801:Humans; D008668:Metallothionein / Q000502:physiology; D008954:Models, Biological; D008958:Models, Molecular; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology; D013329:Structure-Activity Relationship; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013879:Thioredoxins / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000502:physiology; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers / Q000502:physiology*
D000975:Antioxidants; D002614:Chelating Agents; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D013439:Sulfhydryl Reagents; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D013879:Thioredoxins; D004247:DNA; D008668:Metallothionein; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D015032:Zinc