The interaction of adenovirus E1A with p300 family members modulates cellular gene expression to reduce tumorigenicity.
The use of adenovirus serotype 2 or 5 (Ad2/5) E1A as therapy for human malignancy requires an understanding of the mechanisms involved in E1A-induced tumor suppression. The prevailing use of E1A in the treatment of human malignancy stresses the non-immunologically mediated, anti-tumorigenic activities of E1A. However, the capacity of E1A to elicit a NK-cell and T-cell anti-tumor immune response and to sensitize tumor cells to lysis by immune effector molecules utilized by NK cells and T cells is also an important component of the anti-tumorigenic activity of E1A. This immune-mediated anti-tumorigenic activity of E1A is not shared by functionally similar viral oncoproteins such as the human papillomavirus type 16 (HPV16) E7 oncoprotein and is dependent on the capacity of E1A to interact with transcriptional coadapter, p300. To further define the molecular mechanisms whereby E1A reduces tumorigenicity, we compared total cellular gene expression in H4 cells, a human fibrosarcoma cell line, to gene expression in H4 cells stably expressing E1A, E7, or mutant forms of E1A that do not bind p300. The expression of E1A, but not E7, in H4 cells modulated the expression of cellular genes that may promote apoptosis, enhance immunogenicity and reduce tumor cell metastasis. The difference in the ability of E1A and E7 to modulate the expression of cellular genes that may influence tumorigenicity was largely attributable to distinct interactions of E1A and E7 with p300. Results of this study will be useful in designing novel strategies to augment the anti-tumorigenic activities of E1A.
Miura
Tanya A
TA
Department of Microbiology, University of Colorado Health Sciences Center, Aurora, CO, USA.
Cook
James L
JL
Potter
Terence A
TA
Ryan
Sharon
S
Routes
John M
JM
D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D016212:Transforming Growth Factor beta; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human