Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1997-12-12
1999-11-16
Eisenschenk, Chris
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4241861, 4241991, 4242041, 536 2372, 536 235, 4352351, 4353201, 435 5, 435 6, A61K 3923, A61K 3912, C12N 700, C12N 1500
Patent
active
059852836
DESCRIPTION:
BRIEF SUMMARY
This is a Rule 371 application based on the priority date of PCT/GB96/01413, filed Jun. 14, 1996.
This invention relates to a novel suppressor of transactivation.
In particular, the invention relates to BS69, a novel adenovirus E1A-associated protein which inhibits E1A transactivation. This protein can bind to the known viral transcription factors, adenovirus E1A, and can thus suppress the ability of the E1A factors to activate transcription. Hence BS69 can inhibit viral replication and may find use as an anti-adenoviral agent.
The adenovirus E1A gene products are nuclear phosphoproteins that can transactivate other adenovirus early genes as well as several cellular genes, and can transform primary rodent cells in culture. Transformation and transactivation by E1A proteins is most likely mediated through binding to several cellular proteins including the retinoblastoma gene product pRb, the pRb-related p107 and p130, and the TATA box binding protein TBP.
In transformed cells, early region 1A (E1A) of human adenoviruses encode two mRNAs that specify proteins of 243 and 289 amino acids respectively (243R and 289R E1A). E1A proteins can transform primary rodent cells in culture (Houweling et al., 1980) and they stimulate the expression of other early viral genes (Jones and Shenk, 1979) and some cellular genes (Shenk and Flint, 1991). E1A proteins of different serotypes share three regions of significant homology (conserved region (CR) 1, 2 and 3, Lillie et al., 1987). The 243R and the 289R E1A proteins share CR1 and 2, while CR3 is unique in the 289R E1A. CR3 consists of 46 amino acids and specifies a strong transactivation domain (Martin et al., 1990; Green et al., 1988; Lillie and Green, 1989). Activation of gene expression was also detected by the 243R E1A protein (Simon et al., 1987) and by domains encoded by exon 2 of Ad5 E1A (Myrnryk and Bayley, 1993). CR1 and 2 are involved in transformation (Lillie et al., 1987; Whyte et al., 1989), suppression of enhancer activity (Borelli et al., 1984; Velcich and Ziff, 1985; Wang et al., 1993) and the induction of DNA synthesis (Howe and Bayley, 1992; Lillie et al., 1987; Wang et al., 1991).
CR1 and CR2 are thought to exert their effect on cellular physiology by interacting with a number of cellular proteins (Barbeau et al., 1994; Egan et al., 1987; Harlow et al., 1986; Yee and Branton, 1985). Several of these cellular E1A-binding proteins have now been identified. They include the retinoblastoma gene product pRb (Whyte et al., 1988), the pRb-like proteins p107 (Whyte et al., 1989; Zhu et al., 1993) and p130 cannon et al., 1993; Li et al., 1993), cyclin A (Pines and Hunter, 1990) and p300 (Eckner et al., 1994). However, several additional cellular polypeptides have been identified in E1A immunoprecipitates of adenovirus-transformed or adenovirus-infected cells. They include proteins of 30, 33, 75, 95, 150, 180 and >250 kDa molecular weight (Egan et al., 1987). Since several of the presently identified E1A-interacting proteins play important roles in either cell cycle control or transcriptional regulation, the isolation of additional E1A-interacting cDNAs could be of considerable interest.
E1A can transactivate by several distinct mechanisms. First, E1A can activate adenovirus early region 2 (E2) transcription by dissociation of the E2F transcription factor from pRb, thereby activating E2F (Bagchi et al., 1990; Bandara and La Thangue, 1991). It is likely that E1A can also activate the expression of several cellular genes by competing pRb, p107 or p130 from inactive E2F complexes (Bagchi et al., 1990). This activity requires conserved regions 1 and 2 of E1A and is independent of the activation domain that is specified by CR3 (Moran et al., 1986). Secondly, E1A can be recruited to promoters through direct binding to sequence-specific DNA binding proteins. For example, E1A can bind directly to the ATF2 transcription factor, which recruits E1A to the E3 promoter (Liu and Green, 1990, 1994; Maguire et al., 1991). Finally, the large (289R) E1A protein as well as a numb
REFERENCES:
EMBO Journal, vol. 14, No. 13, Jul. 3, 1995, Eynsham, Oxford GB, pp. 3159-3169, XP000579801 Hateboer, R. et al.: "BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation" see the whole document.
Nature Genetics, vol. 4, 1993, pp. 373-380, XP000600257 Adams, M.D. et al.: "Rapid cDNA sequencing (expressed sequence tags) from a directionally cloned human infant brain cNDA library" see table 1 & EMBL EST6, Accession No. T08073, sequence reference EST05964, Aug.-05-1993 Homo sapiens cNDA clone HIBAB61 5'end.
Comptes Rendus Des Seances De L'Academie Des Sciences Serie III: Sciences De La Vie., vol. 318, 1995, Montreuil FR, pp. 263-272, XP000579830 Aufray, C. et al.: "Image: integrated molegular analysis of the human genome and its expression" see the whole document & EMBL EST5, Accession No. Z44907, Sequence reference Hsc2ce021, Nov.-06-1994, H. Sapiens partial cDNA sequence; clone c-2ce02.
Proceedings of the National Academy of Sciences of USA, vol. 90, No. 18, 1993, Washington US, pp. 8489-8493, XP000579826 Hateboer, G. et al.: "TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-myc and adnovirus E1A protein" see the whole document.
Egan et al. 1987, Virology, vol. 160, pp. 292-296, 1987.
Bernards Rene
Hateboer Guus
Eisenschenk Chris
Prolifix Limited
Salimi Ali R.
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