Cell cycle regulation by Kaposi's sarcoma-associated herpesvirus K-bZIP: direct interaction with cyclin-CDK2 and induction of G1 growth arrest.
In order to cope with hostile host environments, many viruses have developed strategies to perturb the cellular machinery to suit their replication needs. Some herpesvirus genes protect cells from undergoing apoptosis to prolong the lives of infected cells, while others, such as Epstein-Barr virus Zta, slow down the G(1)/S transition phase to allow ample opportunity for transcription and translation of viral genes before the onset of cellular genomic replication. In this study, we investigated whether Kaposi's sarcoma-associated herpesvirus (KSHV) K-bZIP, a homologue of the Epstein-Barr virus transcription factor BZLF1 (Zta), plays a role in cell cycle regulation. Here we show that K-bZIP physically associates with cyclin-CDK2 and downmodulates its kinase activity. The association can be detected in the natural environment of KSHV-infected cells without artificial overexpression of either component. With purified protein, it can be shown that the interaction between K-bZIP and cyclin-CDK2 is direct and that K-bZIP alone is sufficient to inhibit CDK2 activity. The interacting domain of K-bZIP has been mapped to the basic region. The result of these associations is a prolonged G(1) phase, accompanied by the induction of p21 and p27 in a naturally infected B-cell line. Thus, in addition to the previously described transcription and genome replication functions, a new role of K-bZIP in KSHV replication is identified in this report.
Izumiya
Yoshihiro
Y
Department of Biological Chemistry, School of Medicine, University of California, Davis, UC Davis Cancer Center, Sacramento, California 95817, USA.
Lin
Su-Fang
SF
Ellison
Thomas J
TJ
Levy
Alon M
AM
Mayeur
Greg L
GL
Izumiya
Chie
C
Kung
Hsing-Jien
HJ
D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology; D015870:Gene Expression; D005814:Genes, Viral; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D017384:Sequence Deletion; D014162:Transfection; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology
D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C118265:K8 protein, Human herpesvirus 8; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases