Biological Sciences Columbia University
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Carol Prives
DA Costa Professor
Mutation of the p53 tumor suppressor gene is the most frequent lesion detected in cancer. Consequently, understanding the structure and function of the normal p53 protein and how it differs from the mutant p53 proteins that are commonly found in cancer patients' tumors should provide valuable information. P53 sits at the nexus of a complex network of signals from agents of stress such as DNA damage or hypoxia and many others. P53 transmits these signals to genes that control cell cycle arrest, programmed cell death, angiogenesis and additional processes. It is well established that p53 functions as a DNA binding protein that can activate or repress transcription from numerous genes involved in the above processes. We have analyzed in detail the functional domains of p53 and how they are regulated by both covalent and non-covalent modifiers. The most well studied regulator of p53 is the Mdm2 protein that is itself a transcriptional target of p53. Interestingly, as well, two related genes p63 and p73 share structural and functional similarities with p53 yet their roles as tumor suppressors are unclear. Our laboratory is currently addressing the following questions about these important proteins:

How do cells transmit signals from genotoxic stress to activate p53? Our experiments have focused on the checkpoint kinases Chk1 and Chk2 and their ability to regulate p53 and p73. In some human cells, however, p53 is induced in the absence of Chk1or Chk2, whilst in others Chk2 appears to be important for p53 activation. We would like to identify factors and kinases that regulate p53 when Chk2 is not involved. We are also studying the regulation of the checkpoint kinases by upstream factors to learn more about their roles in mediating the DNA damage checkpoint response.

How is the p53/Mdm2 circuit regulated? One of the key interactors with p53 is the Mdm2 protein that inhibits p53 by multiple mechanisms. Understanding the relationship between Mdm2 and p53 is currently being actively studied in our laboratory. Interestingly Mdm2 |is itself extensively regulated by stress and other signals in cells. We have found that two homologous proteins cyclin G1 and G2 can each regulate this circuit but appear to function by distinct mechanisms. We are also investigating how p53 and Mdm2 localize to cellular sub-compartments.

What are the roles of the p63 and p73 genes and how are their protein products regulated? We found that a subset of tumor-derived mutant forms of p53 can down-regulate the normally active forms of p63 and p73. This may partially explain why in some cases mutant forms of p53 appear to serve as pro-oncogenic factors. We seek to clarify when and how mutant p53 proteins regulate p63/p73 proteins and whether this is important to tumorigenesis. We are also in the process of identifying cellular proteins that interact specifically with p63 and p73 and how these interactions affect their functions.

How does p53 promote apoptosis? In some tumor cells p53 will not promote apoptosis unless cells are treated with DNA damaging agents and we hope to determine the mechanism by which such agents facilitate cell death mediated by p53. We have also studied apoptosis caused by a transcriptionally impaired mutant form of p53 and found that there are significant differences as well as similarities when compared to apoptosis caused by wild-type p53.

Finally, with respect to the central role that p53 plays in human cancer, can we use information derived from the basic research on this protein to develop p53-based cancer therapeutics? The search for answers to these and other questions are the basis for much of the work currently going on in our laboratory.

MedLine Listing of Dr. Prives's Publications
Representative Publications
  • Ahn J, Urist M, Prives C (2003 ) Questioning the role of checkpoint kinase 2 in the p53 DNA damage response J Biol Chem 278(23): 20480-9. Article
  • Gaiddon C, Lokshin M, Gross I, Levasseur D, Taya Y, Loeffler JP, Prives C (2003 ) Cyclin-dependent Kinases Phosphorylate p73 at Threonine 86 in a Cell Cycle-dependent Manner and Negatively Regulate p73 J Biol Chem 278(30): 27421-27431. Article
  • Ahn J, Prives C (2002 ) Checkpoint kinase 2 (Chk2) monomers or dimers phosphorylate Cdc25C after DNA damage regardless of threonine 68 phosphorylation J Biol Chem 277(50): 48418-26. Article
  • McKinney K, Prives C (2002 ) Efficient specific DNA binding by p53 requires both its central and C-terminal domains as revealed by studies with high-mobility group 1 protein Mol Cell Biol 22(19): 6797-808. Article
  • Urist M, Prives C (2002 ) p53 leans on its siblings Cancer Cell 1(4): 311-3. Article
  • Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS, Prives C (2002 ) Cyclin G recruits PP2A to dephosphorylate Mdm2 Mol Cell 9(4): 761-71. Article
  • Baptiste N, Friedlander P, Chen X, Prives C (2002 ) The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells Oncogene 21(1): 9-21. Article
  • Prives C, Manley JL (2001 ) Why is p53 acetylated? Cell 107(7): 815-8. Article
  • Ahn J, Prives C (2001 ) The C-terminus of p53: the more you learn the less you know Nat Struct Biol 8(9): 730-2. Article
Carol Prives