title: Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins.
abstract: The human cytomegalovirus (HCMV)-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates the retinoblastoma (Rb) tumor suppressor. Here, we identify the other Rb family members p107 and p130 as novel targets of UL97. UL97 phosphorylates p107 and p130 thereby inhibiting their ability to repress the E2F-responsive E2F1 promoter. As with Rb, this phosphorylation, and the rescue of E2F-responsive transcription, is dependent on the L1 LXCXE motif in UL97 and its interacting clefts on p107 and p130. Interestingly, UL97 does not induce the disruption of all p107-E2F or p130-E2F complexes, as it does to Rb-E2F complexes. UL97 strongly interacts with p107 but not Rb or p130. Thus the inhibitory mechanisms of UL97 for Rb family protein-mediated repression of E2F-responsive transcription appear to differ for each of the Rb family proteins. The immediate early 1 (IE1) protein of HCMV also rescues p107- and p130-mediated repression of E2F-responsive gene expression, but it does not induce their phosphorylation and does not disrupt p107-E2F or p130-E2F complexes. The unique regulation of Rb family proteins by HCMV UL97 and IE1 attests to the importance of modulating Rb family protein function in HCMV-infected cells.
authors.affiliation: From the Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Satoko
authors.initials: S
authors.lastname: Iwahori
authors.affiliation: From the Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Angie C
authors.initials: AC
authors.lastname: Umaña
authors.affiliation: From the Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Halena R
authors.initials: HR
authors.lastname: VanDeusen
authors.affiliation: From the Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706 rfkalejta@wisc.edu.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kalejta
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; C493844:RBL1 protein, human; C493837:RBL2 protein, human; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase
keywords: HCMV; cancer; cyclin-dependent kinase (CDK); herpesvirus; oncogene; phosphorylation; tumor suppressor gene