How phosphorylation controls p53

The tumor suppressor p53 is a transcription factor that integrates distinct environmental signals including DNA damage, metabolic stress, oncogene activation, hypoxia and virus infection into a common biological outcome that maintains normal cellular control and tissue integrity. p53 is regulated at the post-translational level by protein-protein interactions and covalent modifications, including phosphorylation at over twenty phosphor-acceptor sites. In this perspective we discuss the function of two evolutionarily conserved p53 phosphorylation motifs, located within the N-terminal transactivation and C-terminal regulatory domains, which have recently been shown to play a tumour suppressive role in stem cell niches. We also consider how mechanisms in addition to phosphorylation by stress-activated kinases can lead to the activation of p53 as a transcription factor, and we review the dual role of p53-activating kinases as tumor suppressors and oncoproteins. Finally, we discuss how changes in the specific activity of p53 can have profound effects not only on cancer development, but also on organism aging.

[1]  T. Hupp,et al.  DAPK-1 Binding to a Linear Peptide Motif in MAP1B Stimulates Autophagy and Membrane Blebbing* , 2008, Journal of Biological Chemistry.

[2]  D. Lane,et al.  Mdm2 and p53 are highly conserved from placozoans to man , 2010, Cell cycle.

[3]  M. Kubbutat,et al.  Regulation of p53 Function and Stability by Phosphorylation , 1999, Molecular and Cellular Biology.

[4]  A. Gudkov,et al.  The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway , 2010, Aging.

[5]  Hong Yang,et al.  Phosphorylation of p53 on Key Serines Is Dispensable for Transcriptional Activation and Apoptosis*♦ , 2004, Journal of Biological Chemistry.

[6]  Stephen N. Jones,et al.  p53 mutant mice that display early ageing-associated phenotypes , 2002, Nature.

[7]  J. Fraser,et al.  A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection* , 2008, Journal of Biological Chemistry.

[8]  T. Hupp,et al.  Identification of a Dominant Negative Functional Domain on DAPK-1 That Degrades DAPK-1 Protein and Stimulates TNFR-1-mediated Apoptosis* , 2007, Journal of Biological Chemistry.

[9]  T. Hupp,et al.  CK2-site Phosphorylation of p53 is Induced in ΔNp63 Expressing Basal Stem Cells in UVB Irradiated Human Skin , 2006, Cell cycle.

[10]  J. Fraser,et al.  The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members , 2007, Molecular and Cellular Biology.

[11]  E. Appella,et al.  Cell Type- and Promoter-specific Roles of Ser18 Phosphorylation in Regulating p53 Responses* , 2003, Journal of Biological Chemistry.

[12]  T. Jacks,et al.  Increased Sensitivity to UV Radiation in Mice with a p53 Point Mutation at Ser389 , 2004, Molecular and Cellular Biology.

[13]  L. Donehower,et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours , 1992, Nature.

[14]  H. K. Sluss,et al.  Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice , 2004, Molecular and Cellular Biology.

[15]  T. Jacks,et al.  Defective apoptosis and B‐cell lymphomas in mice with p53 point mutation at Ser 23 , 2004, The EMBO journal.

[16]  P. Klatt,et al.  Delayed ageing through damage protection by the Arf/p53 pathway , 2007, Nature.

[17]  Gustavo Droguett,et al.  DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation , 2000, Nature Cell Biology.

[18]  G. Blandino,et al.  Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo , 2010, Proceedings of the National Academy of Sciences.

[19]  P. Klatt,et al.  'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally , 2002, The EMBO journal.

[20]  O. Sansom,et al.  Peptide Combinatorial Libraries Identify TSC2 as a Death-associated Protein Kinase (DAPK) Death Domain-binding Protein and Reveal a Stimulatory Role for DAPK in mTORC1 Signaling* , 2009, Journal of Biological Chemistry.

[21]  Stefano Piccolo,et al.  Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation. , 2007, Science.

[22]  F. Gage,et al.  Puma is required for p53-induced depletion of adult stem cells , 2010, Nature Cell Biology.

[23]  T. Jacks,et al.  Lack of p53 Ser389 phosphorylation predisposes mice to develop 2-acetylaminofluorene-induced bladder tumors but not ionizing radiation-induced lymphomas. , 2005, Cancer research.

[24]  S. Gygi,et al.  Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. , 2010, Cancer cell.

[25]  R. Eisenman,et al.  Tumor suppression and normal aging in mice with constitutively high p53 activity. , 2006, Genes & development.

[26]  T. Hupp,et al.  The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway , 2009, Aging.

[27]  Borivoj Vojtesek,et al.  ΔNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation , 2010, Molecular Cancer.

[28]  K. Sabapathy,et al.  Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo , 2011, Cell Death and Differentiation.

[29]  Wei Zhang,et al.  p53 Antiproliferative Function Is Enhanced by Aspartate Substitution at Threonine 18 and Serine 20 , 2002, Cancer biology & therapy.

[30]  D. Eccles,et al.  A Germ Line Mutation in the Death Domain of DAPK-1 Inactivates ERK-induced Apoptosis* , 2007, Journal of Biological Chemistry.

[31]  A. Gudkov,et al.  Paradoxical suppression of cellular senescence by p53 , 2010, Proceedings of the National Academy of Sciences.

[32]  T. Hupp,et al.  CK1α Plays a Central Role in Mediating MDM2 Control of p53 and E2F-1 Protein Stability , 2009, The Journal of Biological Chemistry.

[33]  J. Pennings,et al.  Delayed expression of apoptotic and cell-cycle control genes in carcinogen-exposed bladders of mice lacking p53.S389 phosphorylation. , 2007, Carcinogenesis.

[34]  H. Sheppard,et al.  Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. , 2004, Molecular cell.

[35]  E. Appella,et al.  Mutation of Mouse p53 Ser23 and the Response to DNA Damage , 2002, Molecular and Cellular Biology.

[36]  D. Herr,et al.  Ser18 and 23 phosphorylation is required for p53‐dependent apoptosis and tumor suppression , 2006, The EMBO journal.

[37]  D. Lane,et al.  Small peptides activate the latent sequence-specific DNA binding function of p53 , 1995, Cell.

[38]  Guillermina Lozano,et al.  Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53 , 1995, Nature.

[39]  H. K. Sluss,et al.  The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression. , 2007, Cancer research.

[40]  M. Walkinshaw,et al.  A Novel p53 Phosphorylation Site within the MDM2 Ubiquitination Signal , 2010, The Journal of Biological Chemistry.

[41]  Lawrence A. Donehower,et al.  Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53 , 1995, Nature.

[42]  Wei Zhang,et al.  Enhancement of the antiproliferative function of p53 by phosphorylation at serine 20: an inference from site-directed mutagenesis studies. , 2001, International journal of molecular medicine.