PMID- 20838604
OWN - NLM
STAT- MEDLINE
DCOM- 20110214
LR  - 20211020
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 6
IP  - 9
DP  - 2010 Sep 9
TI  - Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of 
      the conserved herpesvirus protein kinases.
PG  - e1001092
LID - 10.1371/journal.ppat.1001092 [doi]
LID - e1001092
AB  - The UL97 protein of human cytomegalovirus (HCMV, or HHV-5 (human herpesvirus 5)), 
      is a kinase that phosphorylates the cellular retinoblastoma (Rb) tumor suppressor 
      and lamin A/C proteins that are also substrates of cellular cyclin-dependent 
      kinases (Cdks). A functional complementation assay has further shown that UL97 
      has authentic Cdk-like activity. The other seven human herpesviruses each encode 
      a kinase with sequence and positional homology to UL97. These UL97-homologous 
      proteins have been termed the conserved herpesvirus protein kinases (CHPKs) to 
      distinguish them from other human herpesvirus-encoded kinases. To determine if 
      the Cdk-like activities of UL97 were shared by all of the CHPKs, we individually 
      expressed epitope-tagged alleles of each protein in human Saos-2 cells to test 
      for Rb phosphorylation, human U-2 OS cells to monitor nuclear lamina disruption 
      and lamin A phosphorylation, or S. cerevisiae cdc28-13 mutant cells to directly 
      assay for Cdk function. We found that the ability to phosphorylate Rb and lamin 
      A, and to disrupt the nuclear lamina, was shared by all CHPKs from the beta- and 
      gamma-herpesvirus families, but not by their alpha-herpesvirus homologs. 
      Similarly, all but one of the beta and gamma CHPKs displayed bona fide Cdk 
      activity in S. cerevisiae, while the alpha proteins did not. Thus, we have 
      identified novel virally-encoded Cdk-like kinases, a nomenclature we abbreviate 
      as v-Cdks. Interestingly, we found that other, non-Cdk-related activities 
      reported for UL97 (dispersion of promyelocytic leukemia protein nuclear bodies 
      (PML-NBs) and disruption of cytoplasmic or nuclear aggresomes) showed weak 
      conservation among the CHPKs that, in general, did not segregate to specific 
      viral families. Therefore, the genomic and evolutionary conservation of these 
      kinases has not been fully maintained at the functional level. Our data indicate 
      that these related kinases, some of which are targets of approved or 
      developmental antiviral drugs, are likely to serve both overlapping and 
      non-overlapping functions during viral infections.
FAU - Kuny, Chad V
AU  - Kuny CV
AD  - Institute for Molecular Virology and McArdle Laboratory for Cancer Research, 
      University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
FAU - Chinchilla, Karen
AU  - Chinchilla K
FAU - Culbertson, Michael R
AU  - Culbertson MR
FAU - Kalejta, Robert F
AU  - Kalejta RF
LA  - eng
GR  - R01 AI080675/AI/NIAID NIH HHS/United States
GR  - T32 AI078985/AI/NIAID NIH HHS/United States
GR  - AI080675/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100909
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Viral Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
SB  - IM
MH  - Betaherpesvirinae/*enzymology
MH  - Blotting, Western
MH  - Bone Neoplasms/enzymology/genetics/pathology
MH  - Cell Nucleus/enzymology
MH  - Cyclin-Dependent Kinases/genetics/*metabolism
MH  - Cytoplasm/enzymology
MH  - Gammaherpesvirinae/*enzymology
MH  - Herpesviridae Infections/*enzymology/pathology
MH  - Humans
MH  - Nuclear Lamina/enzymology
MH  - Osteosarcoma/enzymology/genetics/pathology
MH  - Phosphorylation
MH  - Phylogeny
MH  - Protein Kinases/genetics/*metabolism
MH  - Retinoblastoma Protein/genetics/metabolism
MH  - Subcellular Fractions
MH  - Tumor Cells, Cultured
MH  - Viral Proteins/genetics/*metabolism
PMC - PMC2936540
COIS- The authors have declared that no competing interests exist.
EDAT- 2010/09/15 06:00
MHDA- 2011/02/15 06:00
PMCR- 2010/09/09
CRDT- 2010/09/15 06:00
PHST- 2009/07/09 00:00 [received]
PHST- 2010/08/09 00:00 [accepted]
PHST- 2010/09/15 06:00 [entrez]
PHST- 2010/09/15 06:00 [pubmed]
PHST- 2011/02/15 06:00 [medline]
PHST- 2010/09/09 00:00 [pmc-release]
AID - 09-PLPA-RA-1146R3 [pii]
AID - 10.1371/journal.ppat.1001092 [doi]
PST - epublish
SO  - PLoS Pathog. 2010 Sep 9;6(9):e1001092. doi: 10.1371/journal.ppat.1001092.