Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-03-10
2001-10-16
Schwartzman, Robert A. (Department: 1636)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S366000, C536S023500
Reexamination Certificate
active
06303335
ABSTRACT:
This invention relates to a novel transcription factor and to its production and uses.
The molecular events that occur during the cell cycle need to be impregnated with the transcription apparatus so that gene expression can be synchronised with cell cycle progression.
Recently, a transcription factor called E2F (or DRTF1) has been identified and shown to bind to pRb, the protein product of the retinoblastoma susceptibility gene, an anti-oncogene or tumour suppressor gene (see for example Wagner and Green, Nature 352, 189-190, 1991). It is widely believed that the cellular transcription factor E2F functions as a key component in cell cycle control because it associates with important cell cycle regulating proteins, such as the retinoblastoma gene product (pRb), p107, cyclins and cyclin-dependent kinases, and furthermore its transcriptional activity is modulated by certain viral oncoproteins, such as adenovirus Ela, SV40 large T antigen, and the human papilloma virus E7 protein.
It is believed that the transcription factor E2F (or DRTF1) plays an important role in integrating cell cycle events with the transcription apparatus because, during cell cycle progression in mammalian cells, it undergoes a series of periodic interactions with molecules that are known to be important regulators of cellular proliferation. For example, the retinoblastoma tumor suppressor gene product (pRb), which negatively regulates progression from G1 into S phase, and is frequently modified in tumour cells, binds to E2F. Similarly, the pRb-related protein p107 occurs predominantly in an S phase complex with E2F. Both pRb and p107 repress the transcriptional activity of E2F, which is likely to be fundamentally important for regulating cellular proliferation because E2F binding sites (the E2F site) occur in the control regions of a variety of genes that are involved with proliferation, such as c-myc and p34
cdc2
. Furthermore, mutant Rb proteins, encoded by alleles isolated from tumour cells, fail to bind to E2F, and hence are unable to interfere with E2F site-dependent transcriptional activation. Another important feature of E2F is that certain viral oncoproteins, such as adenovirus Ela, SV40 large T antigen and human papilloma virus E7, modulate its activity by sequestering pRb and p107 from the inactive transcription factor. This effect requires regions in these viral proteins that are necessary for transformation of tissue culture cells and hence to overcome growth control. Thus, the ability of these oncoproteins to regulate E2F may be the means by which they over-ride the normal mechanisms of cellular growth control and, conversely, transcriptional repression by pRb may be the basis of pRb-mediated negative growth control.
A potential mechanism for integrating the transcription-regulating properties of pRb and p107 with other cell cycle events was suggested by the identification of cyclin A and the cdc2-related cyclin-dependent kinase p33
cdk2
in the E2F complex. Cyclin A is necessary for progression through S phase, a function that could perhaps be mediated through its ability to recruit the cyclin-dependent kinase p33
cdk2
to E2F. Taken together these data suggest that E2F is a transcription factor whose primary role may be to relay cell cycle events to the transcription apparatus via molecules such as pRb, p107, cyclins and cdks, thus ensuring that gene expression is synchronised and integrated with cell cycle progression.
More recently, a transcription factor with the properties of E2F has been cloned and sequenced (Helin et al, Cell 70 (1992), 337-350 and Kaelin et al, Cell 70 (1992), 351-364).
DISCLOSURE OF THE INVENTION
We have now surprisingly found a further new protein which appears to be a new member of the E2F gene family, which we have called E2F-4. The cDNA sequence of E2F-4 is presented in
FIG. 1A
, as is the amino acid sequence of this protein. This new protein is referred to as E2F-4 and this nomenclature will be used in this specification.
It has been found that E2F-4 is one of a family of related transcription factor components. Members of this family are believed to interact with DP proteins to form a series of transcription factors. DP protein (or polypeptides) include DP-1, DP-2 and DP-3 although the first of these will usually be contemplated in preference to the other two.
REFERENCES:
patent: 6045999 (2000-04-01), Bernards et al.
patent: WO 93/15227 (1993-08-01), None
patent: WO 94/10307 (1994-05-01), None
M. Ivey-Hoyle et al., “Cloning and Characterization of E2F-2, a Novel Protein with the Biochemical Properties of Transcription Factor E2F”, Molecular and Cellular Biology, vol. 13, pp. 7802-7812 Dec. 1993.
N. Dyson et al., “Analysis of; 107-Associated Proteins: p107 Associates With a Form of E2F That Differs From pRB-Associated E2F-1”, Journal of Virology, vol. 67, No. 12, pp. 7641-7647 Dec. 1993.
Ayer et al., “Mad: A Heterodimeric Partner for Max That Antagonizes Myc Transcriptional Activity”, Cell, vol. 72, pp. 211-222, Jan. 29, 1993.
Ginsberg et al., “E2F-4, A New Member of the E2F Gene Family, Has Oncogenic Activity and Associates with p107 in vivo”, Genes & Development, vol. 8, No. 22, pp. 2665-2692, Nov. 15, 1994.
Bernards et al., “Identification and Cloning of Proteins that Associate with p107, a Relative of the Retinoblastoma Protein”, (Abstract), EMBL Conference, Heidelberg, Germany Apr. 18-21, 1994.
Beijeersbergen et al., “E2F-4, a New Member of the E2F Gene Family, has Oncogenic Activity and Associates with p107 in vivo”, Genes & Development, vol. 8, No. 22, pp. 2665-2792, Nov. 15, 1994.
Beijersbergen Roderick L.
Bernards Rene
Nixon & Vanderhye P.C.
Prolifix Limited
Schwartzman Robert A.
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