Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2.
Adenovirus type 9 (Ad9) is distinct among human adenoviruses because it elicits solely mammary tumors in animals and its primary oncogenic determinant is the E4 region-encoded ORF1 (E4-ORF1) protein. We report here that the PDZ domain-containing protein ZO-2, which is a candidate tumor suppressor protein, is a cellular target for tumorigenic Ad9 E4-ORF1 but not for non-tumorigenic wild-type E4-ORF1 proteins encoded by adenovirus types 5 and 12. Complex formation was mediated by the C-terminal PDZ domain-binding motif of Ad9 E4- ORF1 and the first PDZ domain of ZO-2, and in cells this interaction resulted in aberrant sequestration of ZO-2 within the cytoplasm. Furthermore, transformation-defective Ad9 E4-ORF1 mutants exhibited impaired binding to and sequestration of ZO-2 in cells, and overexpression of wild-type ZO-2, but not mutant ZO-2 lacking the second and third PDZ domains, interfered with Ad9 E4-ORF1-induced focus formation. Our results suggest that the select capacity to complex with the candidate tumor suppressor protein ZO-2 is key to defining the unique transforming and tumorigenic properties of the Ad9 E4-ORF1 oncoprotein.
Glaunsinger
B A
BA
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Weiss
R S
RS
Lee
S S
SS
Javier
R
R
D017504:Adenovirus E4 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000235:genetics / Q000472:pathogenicity*; D000818:Animals; D019556:COS Cells; D002451:Cell Compartmentation; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000235:genetics*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts; D016147:Genes, Tumor Suppressor; D006801:Humans; D046911:Macromolecular Substances; D008325:Mammary Neoplasms, Experimental / Q000821:virology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005810:Multigene Family; D016366:Open Reading Frames; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D062827:Zonula Occludens-2 Protein
D017504:Adenovirus E4 Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C569046:TJP2 protein, human; D062827:Zonula Occludens-2 Protein