Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-02-29
2001-05-22
Park, Hankyel T. (Department: 1648)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
Reexamination Certificate
active
06235263
ABSTRACT:
BACKGROUND OF THE INVENTION
BRCA1 was the first familial breast and ovarian cancer gene discovered and accounts for approximately 5% of all breast cancer cases (Miki et al., 1994; Cannon-Albright et al., 1996). Currently the mechanisms of tumor suppression by BRCA1 are not well understood. It is plausible that the BRCA1 activities are either regulated or mediated by interactions with other cellular proteins. The disruption of these protein—protein interactions by deleterious mutations in BRCA1 could be one significant step in tumorigenesis. A number of BRCA1 interacting proteins have recently been identified. BARD 1 is a novel protein that binds to the RING finger near the N-terminus of BRCA1 (Wu et al., 1996). Its biological function has not yet been defined, though it is thought to play a role in DNA replication checkpoint control (Scully et al., 1997a; Jin et al., 1997). Certain germline mutations in BRCA1 have been reported to disrupt the interaction with BARD1. Importin-&agr;is a component of the nuclear localization signal (NLS) receptor complex that is believed to associate with the BRCA1 protein (Chen et al., 1996a). It has been proposed that an aberration in the subcellular localization of the BRCA1 protein in breast tumor cells may be a possible mechanism by which the BRCA1 tumor suppressor function is perturbed (Chen et al., 1995). However, questions have been raised about the accuracy of the localization data since conflicting results have been reported by different groups (Thomas et al., 1996; Wilson et al., 1997). RAD51, a homolog to the
E. coli
Rec A protein which is involved in the repair of double-strand DNA breaks, is known to interact with BRCA1 and BRCA2, the second familial breast cancer gene (Shinohara et al., 1992; Tavtigian et al., 1996; Scully et al., 1997b; Sharan et al., 1997). In BRCA2, the sites of RAD51 interaction have been fine mapped to the eight evolutionarily conserved BRC motifs in the internal region of the protein (Wong et al., 1997). The interaction of both breast cancer susceptibility gene products with RAD51 suggests that BRCA1 and BRCA2 participate in the maintenance of genome integrity.
BRCA1 appears to be a multifunctional protein. In addition to a possible role in DNA repair, it has been implicated in the control of cell cycle and cell proliferation (Hakem et al., 1996; Somasundaram et al., 1997) and regulation of transcription (Chapman and Verma, 1996; Monteiro et al., 1996). Scully et al. have shown that BRCA1 is a component of the transcriptionally active RNA polymerase II holoenzyme complex (Scully et al., 1997c). When the carboxy-terminal region of BRCA1 is fused to a heterologous DNA binding domain, transcriptional activation function is observed (Chapman and Verma, 1996; Monteiro et al., 1996). More specifically, BRCA1 can transactivate the expression of cyclin-dependent kinase inhibitor p21 in tissue culture cells resulting in cell cycle arrest at S-phase (Somasundaram et al., 1997). This observation seems to contradict the observation that in knock-out mice p21 over-expression is correlated with the loss of BRCA1 function (Hakem et al., 1996). Some germline mutations at the carboxy-terminal region of BRCA1 are known to abolish the transcriptional activation function (Chapman and Verma, 1996; Monteiro et al., 1996). Yeast two hybrid searches using the carboxy-terminal segment as “bait” to identify interacting proteins that could further our understanding of BRCA1 and the pathway in which it is involved have been conducted and the results are presented here. It is shown that a protein named B112 (or CtIP) is a specific BRCA1 interacting protein. Moreover, the deletion of the last 11 amino acid residues at the carboxy-terminus of BRCA1 by the previously identified 1853ter familial insertion mutation abolishes this protein—protein interaction (Shattuck-Eidens et al., 1995).
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References.
SUMMARY OF THE INVENTION
Sequence conservation at the C-terminal region of the BRCA1 protein among mammalian species suggests some functional significance for that region. Using the yeast two-hybrid and in vitro biochemical assays, it has been found that the partial protein clone B112, which encodes part of the protein known as CtIP (GenBank Accession No. U72066), interacts specifically with a segment of human BRCA1 protein from residues 1602 to 1863. A germline nonsense mutation, 1853ter, that removes the carboxy-terminal 11 amino acids of BRCA1, abolishes not only the transcription activation function of BRCA1, but also binding of BRCA1 to CtIP. The screening of a panel of tumor cell lines has resulted in the identification of a number of missense variants, including a nonconserved lysine to glutamic acid change in the CtIP sequence. Taken together, these results indicate that CtIP and BRCA1 participate in a common biochemical pathway and that the interaction between BRCA1 and CtIP is required for the tumor suppressor activity of BRCA1.
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Callebaut, I. and Mornon, J-P “From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair”,FEBS Letters,1997; 400:25-30.
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Chen, Y. et al. “Aberrant Subcellular Localization of BRCA1 in Breast Cancer”,Science,Nov. 3, 1995; 270:789-791.
Chen, C-F et al. “The Nuclear Localization Sequences of the BRCA1 Protein Interact with the Importin-&agr; Subunit of the Nuclear Transport Signal Receptor”,J. Biol. Chem.,Dec. 20, 1996; 271(51):32863-32868.
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Schaeper, U. et al. “Interaction between a Cellular Protein That Binds to the C-terminal Region of Adenovirus E1A (CtBP) and a Novel Cellular Protein Is Disrupted by E1A through a Conserved PLDLS Motif”,J. Biol. Chem.,Apr. 10, 1998; 273(15):8549-8552.
Scully, R. et al. “Dyn
Bartel Paul L.
Tavtigian Sean V.
Teng David H.-F.
Wong Alexander K. C.
Myriad Genetics Inc.
Park Hankyel T.
Rothwell Figg Ernst & Manbeck
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