Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Patent
1997-07-11
1999-03-23
Elliott, George C.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
530300, C07K 1400, C07K 500
Patent
active
058861505
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel peptide and nucleotide sequences and to their pharmaceutical use. More particularly, the invention relates to peptides which are able to bind to the SH3 domain of the GAP protein.
The products of the Ras genes, generally designated p21 proteins, play a key role in the control of cell division in all the eucaryotic organisms which have been investigated. Certain specific modifications of these proteins cause them to lose their normal control and lead them to become oncogenic. Thus, a large number of human tumours are associated with the presence of modified Ras genes. In the same way, overexpression of these p21 proteins can lead to deregulation of cell proliferation. Taken overall, the p21 proteins are implicated in 30% of human cancers.
An understanding of the precise role of these p21 proteins therefore constitutes one of the main objectives of research in the sphere of oncology.
The model which is currently available for explaining the function of the p21 proteins rests on analogies which they share with the G transduction proteins. In cells, there is an equilibrium between the active p21 proteins, which are bound to GTP, and the inactive forms, which have bound GDP. In a quiescent cell, where the p21 proteins are not required, most of these proteins are in the GDP form. When the cell is stimulated, the nucleotide exchange factor, GEF, becomes more active and promotes removal of the GDP and its replacement by GTP. The protein then adopts an active conformation which enables it to recognize and stimulate its effector, the GAP protein, "GTPase-activating protein", which is in all probability associated with other proteins. The p21-GTP-GAP complex probably interacts, in turn, with one or more other proteins, thereby resulting in transmission of the signal which leads to a biological response by the cell. The association of p21-GTP with GAP simultaneously triggers hydrolysis of the GTP and return of the p21 to its inactive form.
In the case of the oncogenic p21 proteins, the mutation which they carry prevents return to the inactive state. In this latter case, the equilibrium is displaced towards the active form of p21.
This complex equilibrium between the active and inactive forms of p21 is controlled at one and the same time by factors which are inherent to the biochemical properties of the p21 proteins (relative affinity for GDP and GTP, rate of nucleotide exchange, etc.) and external factors which modulate their activity, such as, in particular, the GAP protein.
The GAP protein is a cytosolic protein which is present in all eucaryotic organisms and which possesses, therefore, the property of strongly accelerating hydrolysis of the GTP which is bound to the normal p21 protein (Trahey and McCormick 1987). It possesses two domains which are responsible for separate functions. Its carboxyterminal end carries the catalytic activity which binds the p21 proteins and increases their GTPase activity. At its other end, downstream of the amino terminal part, there is a juxtaposition of domains SH2 and SH3, which are able to participate in interactions with other proteins.
Currently, two proteins are known which interact with the GAP protein. These proteins are designated p62 and p190, being respectively of 62 kDa and 190 kDa molecular weight. Since these two proteins are immunoprecipitated by antibodies directed against different epitopes of GAP, they evidently form a specific complex with GAP. It is known, in particular, that the p62 protein interacts with the GAP protein in the SH2 region.
As far as the SH3 domain is concerned, in particular, its presence in various proteins such as the C.gamma. phospholipases (PLC-.gamma.), the p85 subunit of 3-phosphatidylinositol kinase and the grb-2 protein, all of which are implicated in transduction of the Ras p21 signal, suggests that this domain is of particular importance for directing protein/protein interactions and therefore essential to the function of the corresponding protein and/or its location in the cell. In the particular
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Duchesne Marc
Faucher Didier
Parker Fabienne
Schweighoffer Fabien
Tocque Bruno
Elliott George C.
Rhone-Poulenc Rorer SA
Wang Andrew
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