The vaccinia virus B1R kinase induces p53 downregulation by an Mdm2-dependent mechanism.
Poxvirus infection has a strong effect on cellular functions. To understand viral pathogenesis, it is necessary to know how viral proteins interact with host proteins. The B1R kinase is an early viral gene required for vaccinia virus DNA synthesis and replication, but no cellular substrate is known for this viral kinase. B1R is able to hyperphosphorylate p53 in several residues in the N-terminal transactivation domain, including Ser15 and Thr18. B1R does not phosphorylate Mdm2. B1R promotes an increase in p53 ubiquitination and a reduction of p53 acetylation by p300. The over-expressed B1R protein induces the degradation of p53 in a concentration-dependent manner and is lost when Ser15 and Th18 are changed to alanine or when the B1R kinase is inactivated by introducing the K149Q substitution. The B1R-induced downregulation of p53 requires Mdm2. The hyperphosphorylated p53 is transcriptionally active, and this activity also falls as B1R increases. The BAX gene promoter is more sensitive to this reduction of transcription than p21 or 14-3-3 gene promoters. This effect of B1R on p53 can be one of the mechanisms by which vaccinia virus exerts its role in infected cells.
Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, E-37007 Salamanca, Spain.
Cláudio R
CR
Santos
Francisco M
FM
Vega
Sandra
S
Blanco
Ramiro
R
Barcia
Pedro A
PA
Lazo
D000409:Alanine; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012694:Serine; D013912:Threonine; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D014616:Vaccinia virus / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C074058:VB1R protein, Vaccinia virus; D014764:Viral Proteins; D013912:Threonine; D012694:Serine; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D017346:Protein Serine-Threonine Kinases; D000409:Alanine