Acetylation of p53 Inhibits Its Ubiquitination by Mdm2

Abstract

In response to DNA damage, the activity of the p53 tumor suppressor is modulated by protein stabilization and post-translational modifications including acetylation. Interestingly, both acetylation and ubiquitination can modify the same lysine residues at the C terminus of p53, implicating a role of acetylation in the regulation of p53 stability. However, the direct effect of acetylation on Mdm2-mediated ubiquitination of p53 is still lacking because of technical difficulties. Here, we have developed a method to obtain pure acetylated p53 proteins from cells, and by using an in vitro purified system, we provide the direct evidence that acetylation of the C-terminal domain is sufficient to abrogate its ubiquitination by Mdm2. Importantly, even in the absence of DNA damage, acetylation of the p53 protein is capable of reducing the ubiquitination levels and extending its half-life in vivo. Moreover, we also show that acetylation of p53 can affect its ubiquitination through other mechanisms in addition to the site competition. This study has significant implications regarding a general mechanism by which protein acetylation modulates ubiquitination-dependent proteasome proteolysis. In response to DNA damage, the activity of the p53 tumor suppressor is modulated by protein stabilization and post-translational modifications including acetylation. Interestingly, both acetylation and ubiquitination can modify the same lysine residues at the C terminus of p53, implicating a role of acetylation in the regulation of p53 stability. However, the direct effect of acetylation on Mdm2-mediated ubiquitination of p53 is still lacking because of technical difficulties. Here, we have developed a method to obtain pure acetylated p53 proteins from cells, and by using an in vitro purified system, we provide the direct evidence that acetylation of the C-terminal domain is sufficient to abrogate its ubiquitination by Mdm2. Importantly, even in the absence of DNA damage, acetylation of the p53 protein is capable of reducing the ubiquitination levels and extending its half-life in vivo. Moreover, we also show that acetylation of p53 can affect its ubiquitination through other mechanisms in addition to the site competition. This study has significant implications regarding a general mechanism by which protein acetylation modulates ubiquitination-dependent proteasome proteolysis. CREB-binding protein (where CREB is cAMP-response element-binding protein) histoneacetyl-transferase glutathioneS-transferase dithiothreitol phenylmethylsulfonyl fluoride trichostatin A ubiquitin-activating enzyme ubiquitin carrier protein ubiquitin-protein isopeptide ligase The p53 tumor suppressor exerts antiproliferative effects, including growth arrest, apoptosis, and cell senescence, in response to various types of stress (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google of p53 to to in types of 2000; PubMed Scopus Google p53 is a protein activity is at levels in M. Vousden PubMed Scopus Google regulation of p53 is its effect on cell The mechanism by which p53 is by stress is is to post-translational modifications of p53, including and acetylation (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google that a of p53 and its activity in the of p53 and its activity to the of a activity of on p53 2000; PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google p53 is acetylated at lysine residues of the C-terminal domain by The acetylation of p53 can its DNA a of an Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google acetylated p53 acetylation of p53 in by a of M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google In p53 can also acetylated at by the in to M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, E. 2001; PubMed Scopus Google the levels of acetylated p53 in response to various types of the role of p53 acetylation in stress response Cell. Biol. 2000; PubMed Scopus Google a protein ubiquitination a role in regulation of 2001; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google The ubiquitination of p53 in through the by the protein M. Cell. Full Text PDF PubMed Scopus Google in cells, an ubiquitin ligase and a role in p53 ubiquitination and M. PubMed Scopus Google Scholar, Vousden PubMed Scopus Google Scholar, PubMed Scopus Google in the of the of the lysine is also the ubiquitination 2001; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google have that the lysine residues at the C-terminal domain of p53, of which the acetylation a role in Mdm2-mediated ubiquitination and Cell. Biol. 2000; PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google Scholar, Cell. Biol. 2001; PubMed Scopus Google Scholar, E. Vousden Cell. Biol. 2001; PubMed Scopus Google the levels of p53 acetylation in the cell also p53 from Cell. Biol. 2000; PubMed Scopus Google is to that acetylation of p53 its ubiquitination vivo. However, is direct evidence regarding p53 acetylation its because of the technical difficulties. In we have developed to an mechanism that p53 acetylation is in the regulation of its ubiquitination and by of the in the role of acetylation in the regulation of protein is the pure acetylated the acetylated proteins from the on the of the on acetylated including p53, from the of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google Scholar, M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google Scholar, E. 2001; PubMed Scopus Google is to provide the the and the of proteins the acetylated the provide direct evidence that acetylation of p53 can its ubiquitination by we to obtain the pure of acetylated p53 from Interestingly, that the acetylated p53 protein to of the p53 can by other p53 including also the the C-terminal domain of p53, the acetylation is that acetylation of the C-terminal domain p53 from to the This of an that the p53 can from the acetylated p53 through the the of the acetylated p53 we a to the pure of acetylated p53 from we purified p53 proteins from cell and we the acetylated p53 from the p53 proteins by the in the acetylation levels of p53 the p53 protein in and a the of acetylated p53 using the the p53 proteins purified from cell p53 proteins we on the to the of p53 and the purified acetylated p53 proteins in the purified acetylated p53 by the acetylated acetylated and of p53 to the which is the domain of p53 the purified acetylated p53 protein by the at that acetylation of the p53 protein by can the site the we have the pure of acetylated p53 from from p53 provide the direct evidence that acetylation of p53 its we a p53 ubiquitination by Mdm2. in the and in proteins and purified to and ubiquitin a protein and by a and the a purified protein The purified in vitro in to effect by other on p53 the purified p53 we purified can ubiquitination of an of p53 in in the p53 protein in the of Importantly, in the p53 protein purified from the p53 the same of the acetylated p53 protein by the same that acetylation of p53 its ubiquitination by of p53 its ubiquitination by in of the purified in vitro ubiquitination of the in vitro ubiquitination by the The purified protein of the in on the purified acetylated p53 protein and p53 protein and the The ubiquitination in the of and in the absence of and the we an Interestingly, that the protein the at the acetylation site the acetylated to from and to in M. Cell. Full Text PDF PubMed Scopus Google In a can the acetylated of lysine because of the the and the a in which acetylation Cell. Full Text Full Text PDF PubMed Scopus Google by the the acetylated of Interestingly, have that the at the C-terminal acetylation Mdm2-mediated ubiquitination of the p53 PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google that lysine residues that can by Mdm2. the mechanism by which acetylation of p53 its ubiquitination by acetylation of the p53 C-terminal domain the of acetylated lysine residues and acetylation of p53 also protein to the ubiquitination of lysine residues that the acetylation the we the can Mdm2-mediated ubiquitination of the p53 protein in the the of acetylation ubiquitination a of we a in the same a in which the acetylation by residues of Mdm2-mediated ubiquitination of p53 in vitro by the on the acetylation of the the acetylated lysine and the of the and in vitro ubiquitination of the p53 and p53 proteins by Mdm2. p53 protein protein protein by in vitro and of the ubiquitination we the in vitro p53 proteins the ubiquitination by p53 and in the p53 protein by the protein a on Mdm2-mediated ubiquitination the PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google the on the same lysine residues a to Mdm2-mediated and the ubiquitination levels by the protein the same a effect on Mdm2-mediated ubiquitination by the the effect by the of acetylation of on the that the the acetylated of the lysine the the of the acetylation that acetylation of p53, in addition to the ubiquitination of acetylated lysine also Mdm2-mediated ubiquitination of other lysine through a protein the role of acetylation in the regulation of p53 ubiquitination in we the effect of acetylation on ubiquitination levels of p53 The acetylated p53 protein is from the the DNA to other that also in p53 stabilization the DNA E. 2001; PubMed Scopus Google we to the acetylated of p53 proteins from in levels of p53 proteins in the p53 protein from by a p53 the protein In the p53 in the acetylated of the p53 protein which purified by the from the same we also the effect of acetylation on the half-life of vivo. in the half-life of the p53 protein the acetylated of p53, which a of the p53 protein in cells, the half-life of the acetylated p53 The that acetylation of p53 can abrogate its ubiquitination and the p53 protein effect of acetylation on ubiquitination and of p53 in of the ubiquitination levels of acetylated p53 and p53 proteins from the half-life of the p53 protein from at p53 protein levels by the half-life of the acetylated of the p53 protein in The acetylated p53 proteins the acetylated from the cell at and p53 protein levels by technical we have the that acetylation of p53 ubiquitination-dependent proteolysis. we have also evidence a mechanism on p53 acetylation of p53 the of the acetylated lysine residues also Mdm2-mediated ubiquitination of other lysine through a protein of p53 is its on cell growth and (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google the of in p53 stabilization in response to DNA other types of stress (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, 2000; PubMed Scopus Google is that p53 is at and that p53 stabilization by the and p53 to Mdm2-mediated M. C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. E. M. 2001; PubMed Scopus Google Interestingly, that of on p53 the of DNA to p53 M. Vousden Cell. Biol. PubMed Scopus Google Scholar, C. E. M. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. Vousden Cell. Biol. 2000; PubMed Scopus Google can p53 M. Vousden Cell. Biol. 2000; PubMed Scopus Google the that p53 can the of its domain by by an mechanism by which p53 can through its which the lysine of proteins including and is an in regulation Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google A of the have that acetylation of general protein modifications in regulation of Interestingly, both acetylation and ubiquitination modify the of the lysine Moreover, of acetylated in ubiquitination-dependent proteasome and acetylation lysine residues also ubiquitination 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, E. Cell. Full Text Full Text PDF PubMed Scopus Google study on p53 acetylation also a general mechanism by which protein acetylation modulates the ubiquitination-dependent protein is that the the acetylation and ubiquitination both and of the The p53 tumor suppressor exerts antiproliferative effects, including growth arrest, apoptosis, and cell senescence, in response to various types of stress (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google of p53 to to in types of 2000; PubMed Scopus Google p53 is a protein activity is at levels in M. Vousden PubMed Scopus Google regulation of p53 is its effect on cell The mechanism by which p53 is by stress is is to post-translational modifications of p53, including and acetylation (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google that a of p53 and its activity in the of p53 and its activity to the of a activity of on p53 2000; PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google p53 is acetylated at lysine residues of the C-terminal domain by The acetylation of p53 can its DNA a of an Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google acetylated p53 acetylation of p53 in by a of M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google In p53 can also acetylated at by the in to M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, E. 2001; PubMed Scopus Google the levels of acetylated p53 in response to various types of the role of p53 acetylation in stress response Cell. Biol. 2000; PubMed Scopus Google a protein ubiquitination a role in regulation of 2001; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google The ubiquitination of p53 in through the by the protein M. Cell. Full Text PDF PubMed Scopus Google in cells, an ubiquitin ligase and a role in p53 ubiquitination and M. PubMed Scopus Google Scholar, Vousden PubMed Scopus Google Scholar, PubMed Scopus Google in the of the of the lysine is also the ubiquitination 2001; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google have that the lysine residues at the C-terminal domain of p53, of which the acetylation a role in Mdm2-mediated ubiquitination and Cell. Biol. 2000; PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google Scholar, Cell. Biol. 2001; PubMed Scopus Google Scholar, E. Vousden Cell. Biol. 2001; PubMed Scopus Google the levels of p53 acetylation in the cell also p53 from Cell. Biol. 2000; PubMed Scopus Google is to that acetylation of p53 its ubiquitination vivo. However, is direct evidence regarding p53 acetylation its because of the technical difficulties. In we have developed to an mechanism that p53 acetylation is in the regulation of its ubiquitination and by Mdm2. of the in the role of acetylation in the regulation of protein is the pure acetylated the acetylated proteins from the on the of the on acetylated including p53, from the of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google Scholar, M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google Scholar, E. 2001; PubMed Scopus Google is to provide the the and the of proteins the acetylated the provide direct evidence that acetylation of p53 can its ubiquitination by we to obtain the pure of acetylated p53 from Interestingly, that the acetylated p53 protein to of the p53 can by other p53 including also the the C-terminal domain of p53, the acetylation is that acetylation of the C-terminal domain p53 from to the This of an that the p53 can from the acetylated p53 through the the of the acetylated p53 we a to the pure of acetylated p53 from we purified p53 proteins from cell and we the acetylated p53 from the p53 proteins by the in the acetylation levels of p53 the p53 protein in and a the of acetylated p53 using the the p53 proteins purified from cell p53 proteins we on the to the of p53 and the purified acetylated p53 proteins in the purified acetylated p53 by the acetylated acetylated and of p53 to the which is the domain of p53 the purified acetylated p53 protein by the at that acetylation of the p53 protein by can the site the we have the pure of acetylated p53 from from p53 provide the direct evidence that acetylation of p53 its we a p53 ubiquitination by Mdm2. in the and in proteins and purified to and ubiquitin a protein and by a and the a purified protein The purified in vitro in to effect by other on p53 the purified p53 we purified can ubiquitination of an of p53 in in the p53 protein in the of Importantly, in the p53 protein purified from the p53 the same of the acetylated p53 protein by the same that acetylation of p53 its ubiquitination by the we an Interestingly, that the protein the at the acetylation site the acetylated to from and to in M. Cell. Full Text PDF PubMed Scopus Google In a can the acetylated of lysine because of the the and the a in which acetylation Cell. Full Text Full Text PDF PubMed Scopus Google by the the acetylated of Interestingly, have that the at the C-terminal acetylation Mdm2-mediated ubiquitination of the p53 PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google that lysine residues that can by Mdm2. the mechanism by which acetylation of p53 its ubiquitination by acetylation of the p53 C-terminal domain the of acetylated lysine residues and acetylation of p53 also protein to the ubiquitination of lysine residues that the acetylation the we the can Mdm2-mediated ubiquitination of the p53 protein in the the of acetylation ubiquitination a of we a in the same a in which the acetylation by residues of Mdm2-mediated ubiquitination of p53 in vitro by the on the acetylation of the the acetylated lysine and the of the and in vitro ubiquitination of the p53 and p53 proteins by Mdm2. p53 protein protein protein by in vitro and of the ubiquitination we the in vitro p53 proteins the ubiquitination by p53 and in the p53 protein by the protein a on Mdm2-mediated ubiquitination the PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google the on the same lysine residues a to Mdm2-mediated and the ubiquitination levels by the protein the same a effect on Mdm2-mediated ubiquitination by the the effect by the of acetylation of on the that the the acetylated of the lysine the the of the acetylation that acetylation of p53, in addition to the ubiquitination of acetylated lysine also Mdm2-mediated ubiquitination of other lysine through a protein the role of acetylation in the regulation of p53 ubiquitination in we the effect of acetylation on ubiquitination levels of p53 The acetylated p53 protein is from the the DNA to other that also in p53 stabilization the DNA E. 2001; PubMed Scopus Google we to the acetylated of p53 proteins from in levels of p53 proteins in the p53 protein from by a p53 the protein In the p53 in the acetylated of the p53 protein which purified by the from the same we also the effect of acetylation on the half-life of vivo. in the half-life of the p53 protein the acetylated of p53, which a of the p53 protein in cells, the half-life of the acetylated p53 The that acetylation of p53 can abrogate its ubiquitination and the p53 protein effect of acetylation on ubiquitination and of p53 in of the ubiquitination levels of acetylated p53 and p53 proteins from the half-life of the p53 protein from at p53 protein levels by the half-life of the acetylated of the p53 protein in The acetylated p53 proteins the acetylated from the cell at and p53 protein levels by technical we have the that acetylation of p53 ubiquitination-dependent proteolysis. we have also evidence a mechanism on p53 acetylation of p53 the of the acetylated lysine residues also Mdm2-mediated ubiquitination of other lysine through a protein of p53 is its on cell growth and (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google the of in p53 stabilization in response to DNA other types of stress (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, 2000; PubMed Scopus Google is that p53 is at and that p53 stabilization by the and p53 to Mdm2-mediated M. C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. E. M. 2001; PubMed Scopus Google Interestingly, that of on p53 the of DNA to p53 M. Vousden Cell. Biol. PubMed Scopus Google Scholar, C. E. M. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. Vousden Cell. Biol. 2000; PubMed Scopus Google can p53 M. Vousden Cell. Biol. 2000; PubMed Scopus Google the that p53 can the of its domain by by an mechanism by which p53 can through its which the lysine of proteins including and is an in regulation Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google A of the have that acetylation of general protein modifications in regulation of Interestingly, both acetylation and ubiquitination modify the of the lysine Moreover, of acetylated in ubiquitination-dependent proteasome and acetylation lysine residues also ubiquitination 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, E. Cell. Full Text Full Text PDF PubMed Scopus Google study on p53 acetylation also a general mechanism by which protein acetylation modulates the ubiquitination-dependent protein is that the the acetylation and ubiquitination both and of the of the in the role of acetylation in the regulation of protein is the pure acetylated the acetylated proteins from the on the of the on acetylated including p53, from the of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google Scholar, M. Anderson C.W. E. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google Scholar, E. 2001; PubMed Scopus Google is to provide the the and the of proteins the acetylated the provide direct evidence that acetylation of p53 can its ubiquitination by we to obtain the pure of acetylated p53 from Interestingly, that the acetylated p53 protein to of the p53 can by other p53 including also the the C-terminal domain of p53, the acetylation is that acetylation of the C-terminal domain p53 from to the This of an that the p53 can from the acetylated p53 through the the of the acetylated p53 we a to the pure of acetylated p53 from we purified p53 proteins from cell and we the acetylated p53 from the p53 proteins by the in the acetylation levels of p53 the p53 protein in and a the of acetylated p53 using the the p53 proteins purified from cell p53 proteins we on the to the of p53 and the purified acetylated p53 proteins in the purified acetylated p53 by the acetylated acetylated and of p53 to the which is the domain of p53 the purified acetylated p53 protein by the at that acetylation of the p53 protein by can the site the we have the pure of acetylated p53 from from p53 provide the direct evidence that acetylation of p53 its we a p53 ubiquitination by Mdm2. in the and in proteins and purified to and ubiquitin a protein and by a and the a purified protein The purified in vitro in to effect by other on p53 the purified p53 we purified can ubiquitination of an of p53 in in the p53 protein in the of Importantly, in the p53 protein purified from the p53 the same of the acetylated p53 protein by the same that acetylation of p53 its ubiquitination by Mdm2. the we an Interestingly, that the protein the at the acetylation site the acetylated to from and to in M. Cell. Full Text PDF PubMed Scopus Google In a can the acetylated of lysine because of the the and the a in which acetylation Cell. Full Text Full Text PDF PubMed Scopus Google by the the acetylated of Interestingly, have that the at the C-terminal acetylation Mdm2-mediated ubiquitination of the p53 PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google that lysine residues that can by Mdm2. the mechanism by which acetylation of p53 its ubiquitination by acetylation of the p53 C-terminal domain the of acetylated lysine residues and acetylation of p53 also protein to the ubiquitination of lysine residues that the acetylation the we the can Mdm2-mediated ubiquitination of the p53 protein in the the of acetylation ubiquitination a of we a in the same a in which the acetylation by residues of the ubiquitination we the in vitro p53 proteins the ubiquitination by p53 and in the p53 protein by the protein a on Mdm2-mediated ubiquitination the PubMed Scopus Google Scholar, Cell. Biol. 2000; PubMed Scopus Google the on the same lysine residues a to Mdm2-mediated and the ubiquitination levels by the protein the same a effect on Mdm2-mediated ubiquitination by the the effect by the of acetylation of on the that the the acetylated of the lysine the the of the acetylation that acetylation of p53, in addition to the ubiquitination of acetylated lysine also Mdm2-mediated ubiquitination of other lysine through a protein the role of acetylation in the regulation of p53 ubiquitination in we the effect of acetylation on ubiquitination levels of p53 The acetylated p53 protein is from the the DNA to other that also in p53 stabilization the DNA E. 2001; PubMed Scopus Google we to the acetylated of p53 proteins from in levels of p53 proteins in the p53 protein from by a p53 the protein In the p53 in the acetylated of the p53 protein which purified by the from the same we also the effect of acetylation on the half-life of vivo. in the half-life of the p53 protein the acetylated of p53, which a of the p53 protein in cells, the half-life of the acetylated p53 The that acetylation of p53 can abrogate its ubiquitination and the p53 protein technical we have the that acetylation of p53 ubiquitination-dependent proteolysis. we have also evidence a mechanism on p53 acetylation of p53 the of the acetylated lysine residues also Mdm2-mediated ubiquitination of other lysine through a protein of p53 is its on cell growth and (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google the of in p53 stabilization in response to DNA other types of stress (1Appella E. Anderson C.W. Pathol. Biol. (Paris). 2000; 48: 227-245PubMed Google Scholar, 2Prives C. Manley J.L. Cell. 2001; 107: 815-818Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Ashcroft M. Vousden PubMed Scopus Google Scholar, M. C. M. M. E. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, 2000; PubMed Scopus Google is that p53 is at and that p53 stabilization by the and p53 to Mdm2-mediated M. C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. E. M. 2001; PubMed Scopus Google Interestingly, that of on p53 the of DNA to p53 M. Vousden Cell. Biol. PubMed Scopus Google Scholar, C. E. M. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. Vousden Cell. Biol. 2000; PubMed Scopus Google can p53 M. Vousden Cell. Biol. 2000; PubMed Scopus Google the that p53 can the of its domain by by an mechanism by which p53 can through its acetylation. which the lysine of proteins including and is an in regulation Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google A of the have that acetylation of general protein modifications in regulation of Interestingly, both acetylation and ubiquitination modify the of the lysine Moreover, of acetylated in ubiquitination-dependent proteasome and acetylation lysine residues also ubiquitination 2000; PubMed Scopus Google Scholar, Biol. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar, E. Cell. Full Text Full Text PDF PubMed Scopus Google study on p53 acetylation also a general mechanism by which protein acetylation modulates the ubiquitination-dependent protein is that the the acetylation and ubiquitination both and of the and and technical and in the cell and also other of the of and