Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1995-06-23
1999-01-26
Campbell, Bruce R.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
4353201, 435325, 536 235, 536 2431, 935 9, 935 60, C12N 500, C12N 1500, C07H 2104
Patent
active
058637575
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a novel transcription factor, to its production and uses.
The molecular events that occur during the cell cycle need to be integrated with the transcription apparatus so that gene expression can be synchronised with cell cycle progression. Recently, a transcription factor called DRTF1 or E2F 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 DRTF1/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 vial oncoproteins, such as adenovirus Ela, SV40 large T antigen, and the human papilloma virus E7 protein.
It is believed that the transcription factor DRTF1/E2F 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 tumour suppressor gene product (pRb), which negatively regulates progression from G1 into S phase and is frequently modified in tumour cells binds to DRTF1/E2F. Similarly, the pRb-related protein p107 occurs predominantly in an S phase complex with DRTF1/E2F. Both pRb and p107 repress the transcriptional activity of DRTF1/E2F, which is likely to be fundamentally important for regulating cellular proliferation because DRTF1/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.sup.cdc2. Furthermore, mutant Rb proteins, encoded by alleles isolated from tumour cells, fail to bind to DRTF1/E2F, and hence are unable to interfere with E2F site-dependent transcriptional activation. Another important feature of DRTF1/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 DRTF1/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.sup.cdk2 in the DRTF1/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.sup.cdk2 to DRTF1/E2F. Taken together these data suggest that DRTF1/E2F is a transcription factor whose primary role may be to relay cell cycle events to the transcription apparatus via molecules such a 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).
We have now surprisingly found that the protein termed E2F is a complex of factors, comprising the factor cloned by Helin et al and Kaelin et al, and a novel protein, whose cDNA sequence is presented below as Seq. ID No. 2. The sequence of the cDNA encoding this protein is shown below as Seq. ID No. 1. The new protien is referred to by us as DP-1. While not wishing to be
REFERENCES:
The EMBO Journal vol. 11 No. 7 pp. 2603-2610, 1992 Zamanian et al. "Adenovirus E1a prevents the retinoblastoma gene product from repressing the activity of a cellular transcription factor".
Cell , vol. 70, 351-364, Jul. 24, 1992 Kaelin et al "Expression Cloning of a cDNA Encoding a Retinoblastoma-Binding Protein with E1F-like Properties".
Molecular and Cellular Biology Mar. 1991, pp. 1686-1695 vol. 11, No. 3 Shivji et al "Multicomponent Differentiation-Regulated Transcription Factors in F9 Embryonal Carcioma Stem Cells".
Letters to Nature vol. 362, pp. 83-87 Mar. 4, 1993 Girling et al "A new component of the transcription factor DRTF1/E2F".
Current Biology 1993, vol. 3 No. 8, pp. 554-557 La Thangue et al "Transcriptional complexity".
Genes & Development 7i1850-1861 1993 Helin et al "Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation".
Bekkers et al (1991) Biochimica Biophysica Acta 1089: 345-351.
Madeline et al (1986) 83: 6761-6765.
Marshall, E (1995) Science 269: 1050-1055.
Miller et al (1995) FASEB. J. 9:190-199.
Crystal, R.G. (1995) Science 270: 404-410.
Watson et al (1987) Molecular Biology of the Gene, Fourth Edition, vol. 1, p. 313.
Campbell Bruce R.
Medical Research Council
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