The NH(2)-terminal and conserved region 2 domains of adenovirus E1A mediate two distinct mechanisms of tumor suppression.
Adenovirus E1A has been shown to suppress tumor growth and induce apoptosis in response to stress. To determine the mechanisms and regions of E1A that mediate these functions, we characterized stable transfectants of various E1A mutants in murine melanoma cells both in vitro and in vivo. Three E1A-mutant constructs were used in this study, those having a single deletion at either the NH(2)-terminal (dl1101) or conserved region 2 (CR2) domain (dl1108), or double deletions at both domains (dl0108). The in vitro study showed that the CR2 domain is required for E1A-mediated apoptosis, whereas the NH(2)-terminal domain is dispensable. The in vivo study showed that dl1101 and dl1108 were still able to suppress tumor growth, whereas dl0108 lost tumor-suppressive activity. By in situ immunohistostaining, we found that factor VIII, a marker for angiogenesis, was greatly suppressed in dl1108 transfectants that are resistant to apoptosis. Thus, inhibition of angiogenesis is involved in the NH(2)-terminal domain of E1A. In conclusion, we suggest that the NH(2)-terminal and CR2 domain of E1A mediate two distinct mechanisms of tumor suppression.
Deng
Jiong
J
Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kloosterbooer
Freke
F
Xia
Weiya
W
Hung
Mien-Chie
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D017124:Conserved Sequence; D005260:Female; D016147:Genes, Tumor Suppressor; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000378:metabolism; D014162:Transfection
D017500:Adenovirus E1A Proteins; D016160:Retinoblastoma Protein