Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1994-10-17
1998-12-01
Elliott, George C.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
4353201, 436 89, 530350, 536 235, C12Q 168, C12N 1563, C07H 2104, C07K 1447
Patent
active
058436464
DESCRIPTION:
BRIEF SUMMARY
This invention broadly relates to polynucleotides encoding mammalian Sos gene and protein product thereof.
Protein tyrosine kinases (PTKs) are important regulatory proteins that control many aspects of cellular growth, differentiation, and metabolism (Cantley et al., 1991). Many polypeptide hormones are known to regulate the metabolism, differentiation, and growth of target cells by binding transmembrane receptors that possess intracellular PTK domains (Cross and Dexter, 1991).
The biological effects of PTK activation throughout mammalian cells may be mediated, at least in part, via the Ras proteins (Simon et al., Cell, Vol. 67, 701-716). Ras genes and protein products are associated with a variety of human tumours, particularly where Ras is overproduced or inappropriately expressed.
Simon et al. (Supra) identified a Drosophila gene, associated with protein tyrosine kinase signalling. The Drosophila son of sevenless (Sos) gene product is homologous to a yeast protein (CDC25), which is an activator of guanine nucleotide exchange by Ras proteins. The data of Simon et al. (Supra) indicates that tyrosine kinase signalling is effected by activation of the Sos protein (such as via tyrosine phosphorylation, or some form of indirect stimulation), which then activates Ras proteins by exchange GDP for GTP.
We have surprisingly identified the mammalian Sos gene, hereinafter referred to as mSos, fragments thereof, which have homology to various guanine exchange factors.
In accordance with a first aspect of this invention, there is provided a polynucleotide encoding an mSos gene, or a fragment or analogue thereof. This invention includes any mammalian Sos including human, domestic animal (sheep, cattle, etc) and companion animal (cats, dog, etc) mSos.
The term polynucleotide as referred to herein refers to DNA and RNA, and derivatives thereof as are well known in the art
Partial nucleotide sequences of the murine mSos genes mSos1 (SEQ ID NO:1) and mSos2 (SEQ ID NO:3) are shown in FIGS. 1 and 2. This invention includes such polynucleotide sequences and their full length equivalents, as well as analogues thereof where one or more nucleotides are substituted, deleted or inserted. Methods for the generation of polynucleotide analogues are well known in the art.
This invention includes vectors, such as plasmid, viral or other vectors as are well known in the art, which include a polynucleotide encoding mSos or a fragment or analogue thereof.
In another aspect of this invention, there is provided an mSos polypeptide or fragment or analogue thereof. The amino acid sequence of two murine mSos polypeptides, referred to as mSos 1 (SEQ ID NO:2) and mSos 2 (SEQ ID NO:4) are shown in FIGS. 1 and 2, compared to the drosophila Sos protein product. This invention extends to any mammalian mSos polypeptide, fragment or analogue thereof, including human, domestic animal and companion animal mSos polypeptide.
Reference to mSos polynucleotide fragments, or mSos polypeptide fragments, is to be taken to mean fragments which are unique to mSos. Such fragments will generally comprise in excess of twenty nucleotides, or 20 amino acids, and in particular correspond to a central domain of about 430 amino acids, which is homologous to a number of yeast guanine nucleotide exchange factors (as depicted in FIGS. 3a and 3b (SEQ ID NOS:1 and 3)).
Analogues of mSos polypeptides include amino acid modifications, deletions, substitutions, derivitizations and insertions of one or more amino acids.
It is stressed that this invention extends to mammalian Sos (mSos), in particular human. While this invention is exemplified with reference to murine Sos, the invention is clearly not so limited. Reference to mSos means any mammalian Sos gene or polypeptide, which may be isolated and characterised in accordance with this invention. For example, human mSos polynucleotides may be isolated by hybridization of murine mSos polynucleotides or fragments thereof to human cDNA or genomic sequences followed by isolation and characterisation of hybridising species. Mammals
REFERENCES:
Bonfini et al. (Jan. 1992) Science 255:603-606.
Bowtell (Jul. 1992) Proc. Natl. Acad. Sci. USA 89:6511-6515.
Elliott George C.
Howard Florey Institute of Experimental Physiology and Medicine
Schwartzman Robert
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