Role of human cytomegalovirus immediate-early proteins in cell growth control.
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been implicated in several disorders, including an association between HCMV reactivation and the overproliferation of arterial smooth muscle cells observed in restenosis. Although HCMV can mediate a growth-arrest phenotype in infected cells, the virus can also promote an environment conducive to proliferation. Here, we present evidence that the HCMV immediate-early (IE) proteins, IE1-72 and IE2-86, may be responsible for inducing this proliferative environment by altering cell cycle control. We find that expression of either of these IE proteins can alter the cell cycle distribution of randomly cycling cells towards S and G(2)/M phases. Additionally, we find that expression of IE2-86, but not IE1-72, induces quiescent cells into S phase and delays cell cycle exit. In the absence of p53, IE1-72 expression can induce S phase and delay cell cycle exit. We also demonstrate that p53 protein levels increase in fibroblasts following the expression of IE1-72. The observed accumulation of p53 protein in IE1-72-expressing cells may account for the inability of IE1-72 to induce S phase and delay cell cycle exit. Our data suggest that expression of HCMV IE1-72 and IE2-86 is sufficient to alter the cell cycle to generate an environment conducive to proliferation.
Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
J P
JP
Castillo
A D
AD
Yurochko
T F
TF
Kowalik
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D003587:Cytomegalovirus / Q000378:metabolism*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D005434:Flow Cytometry; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins; D051381:Rats; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014759:Viral Envelope Proteins; D014764:Viral Proteins
C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C077406:UL115 protein, Human herpesvirus 5; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C071440:glycoprotein H, Cytomegalovirus; C499358:glycoprotein H, Human cytomegalovirus; C439068:glycoprotein O, cytomegalovirus