ArticleThe Journal of biological chemistry2015
Molecular Determinants for the Inactivation of the Retinoblastoma Tumor Suppressor by the Viral Cyclin-dependent Kinase UL97.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- Identification of a New Phosphorylated Host Interactor of the Epstein-Barr Virus (EBV) Kinase BGLF4 Suggests Key Points for EBV-Specific Antiviral Drug Targeting.International journal of molecular sciences · 2026Article
- Review
- Review
- Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses.Viruses · 2022Article
- Highly Conserved Interaction Profiles between Clinically Relevant Mutants of the Cytomegalovirus CDK-like Kinase pUL97 and Human Cyclins: Functional Significance of Cyclin H.International journal of molecular sciences · 2022Article
- Virus-host protein interactions as footprints of human cytomegalovirus replication.Current opinion in virology · 2022Review
- Mechanism of herpesvirus protein kinase UL13 in immune escape and viral replication.Frontiers in immunology · 2022Review
- Emerging Mechanisms of GmBio · 2021Review
- Functional Relevance of the Interaction between Human Cyclins and the Cytomegalovirus-Encoded CDK-Like Protein Kinase pUL97.Viruses · 2021Article
- Overview of Human Cytomegalovirus Pathogenesis.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Cross-regulation of viral kinases with cyclin A secures shutoff of host DNA synthesis.Nature communications · 2020Article
- Mass Spectrometry-Based Characterization of the Virion Proteome, Phosphoproteome, and Associated Kinase Activity of Human Cytomegalovirus.Microorganisms · 2020Review
- Human Cytomegalovirus Primary Infection and Reactivation: Insights From Virion-Carried Molecules.Frontiers in microbiology · 2020Review
- Conserved Herpesvirus Protein Kinases Target SAMHD1 to Facilitate Virus Replication.Cell reports · 2019Article
- Cyclins B1, T1, and H differ in their molecular mode of interaction with cytomegalovirus protein kinase pUL97.The Journal of biological chemistry · 2019Article
- Interpretation of EBV infection in pan-cancer genome considering viral life cycle: LiEB (Life cycle of Epstein-Barr virus).Scientific reports · 2019Article
- Activation of E2F-dependent transcription by the mouse cytomegalovirus M117 protein affects the viral host range.PLoS pathogens · 2018Article
- Direct Substrate Identification with an Analog Sensitive (AS) Viral Cyclin-Dependent Kinase (v-Cdk).ACS chemical biology · 2018Article
- Article
- Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins.The Journal of biological chemistry · 2017Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The retinoblastoma (Rb) tumor suppressor restricts cell cycle progression by repressing E2F-responsive transcription. Cellular cyclin-dependent kinase (CDK)-mediated Rb inactivation through phosphorylation disrupts Rb-E2F complexes, stimulating transcription. The human cytomegalovirus (HCMV) UL97 protein is a viral CDK (v-CDK) that phosphorylates Rb. Here we show that UL97 phosphorylates 11 of the 16 consensus CDK sites in Rb. A cleft within Rb accommodates peptides with the amino acid sequence LXCXE. UL97 contains three such motifs. We determined that the first LXCXE motif (L1) of UL97 and the Rb cleft enhance UL97-mediated Rb phosphorylation. A UL97 mutant with a non-functional L1 motif (UL97-L1m) displayed significantly reduced Rb phosphorylation at multiple sites. Curiously, however, it efficiently disrupted Rb-E2F complexes but failed to relieve Rb-mediated repression of E2F reporter constructs. The HCMV immediate early 1 protein cooperated with UL97-L1m to inactivate Rb in transfection assays, likely indicating that cells infected with a UL97-L1m mutant virus show no defects in growth or E2F-responsive gene expression because of redundant viral mechanisms to inactivate Rb. Our data suggest that UL97 possesses a mechanism to elicit E2F-dependent gene expression distinct from disruption of Rb-E2F complexes and dependent upon both the L1 motif of UL97 and the cleft region of Rb.
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