A G1 cell cycle arrest induced by ligands of the reovirus type 3 receptor is secondary to inactivation of p21ras and mitogen-activated protein kinase.
The reovirus type 3 S1 gene product (type 3 hemagglutinin; HA3) is the viral protein responsible for binding to a mammalian cell-surface receptor. It has been shown that HA3 binding to its receptor inhibits cell growth, even in the continuous presence of serum mitogens. Here, receptor-mediated signal transduction leading to growth arrest was studied after binding with synthetic or recombinant ligands in the absence of viral infection. Receptor ligation caused rapid inactivation of p21(ras), a decrease in Raf phosphorylation and in mitogen-activated protein kinase (MAPK) enzymatic activity, and G1 cell cycle arrest. Transfection and expression of constitutively active v-Has-ras prevented the G1 arrest, indicating that inactivation of p21(ras) is causative. Interestingly, v-Has-ras expression also decreased the efficiency of reoviridae replication, suggesting that inactivation of p21(ras) signals is required at some step of the viral cycle. This study may define new mechanisms regulating cell growth and support the approach of using viral proteins to identify and study cellular receptors. Synthetic receptor ligands with antiproliferative properties may be useful in drug development with the aim of blocking mitosis.
Saragovi
H U
HU
Department of Pharmacology, McGill Cancer Center, McGill University, Montréal, Québec, Canada.
Rebai
N
N
Di Guglielmo
G M
GM
Macleod
R
R
Sheng
J
J
Rubin
D H
DH
Greene
M I
MI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D036022:Capsid Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral; D016193:G1 Phase / Q000187:drug effects*; D011905:Genes, ras; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000502:physiology*; D011991:Receptors, Virus / Q000819:agonists / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects
D000911:Antibodies, Monoclonal; D036022:Capsid Proteins; D018797:Cell Cycle Proteins; D006131:Growth Inhibitors; D008024:Ligands; D010456:Peptides, Cyclic; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C400208:Reo3Y protein, Mammalian orthoreovirus 3; D014764:Viral Proteins; C046176:reovirus type 3 receptor; C031728:sigma 1 protein, reovirus; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)