NASA Scientific and Technical Aerospace Reports

20040111619 Pennsylvania Univ., Philadelphia, PA
Structural Basis for the Pharmacological Rescue of Mutant p53 With Small Molecule Compounds
Ho, William C.; Apr. 2004; 11 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0629
Report No.(s): AD-A425714; No Copyright; Avail: CASI; A03, Hardcopy
The p53 protein is a tumor suppressor crucial to maintaining genomic integrity. In the event of DNA damage, p53 is
responsible for transcribing genes leading to cell death. A class of mutations which occur in the core domain (102-292) leads
to thermodynamic destabilization and inability to bind its cognate DNA sequence. Small molecules which bind to and stabilize
mutant p53 core domain have potential to be therapeutically useful. Two potential ‘hot spots’ on the surface of the mouse p53
core domain have been discovered which can be targeted by small molecule compounds. One hot spot was discovered by
soaking the crystal lattice with various organic solvents, and locating the solvents in the electron density. Another potential
hot spot was located in the high resolution structure of the mouse core domain where a molecule of
tris(hydroxymethyl)aminomethane (Tris) was observed to bind on the surface of the protein, making numerous hydrogen
bonding contacts. The design and synthesis of molecules which bind to these areas is currently ongoing.
DTIC
Cancer; Damage; Deoxyribonucleic Acid; Pharmacology; Rescue Operations
20040111620 Winston-Salem State Univ., Winston-Salem, NC
Mechanism of FADD-DN-Induced Apoptosis in Normal Breast Cells
Thomas, Lance R.; Apr. 2004; 7 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0611
Report No.(s): AD-A425715; No Copyright; Avail: CASI; A02, Hardcopy
Normal cells undergo apoptosis in response to inappropriate growth signals or the lack of oven survival signals. Tumor
cells possess defects in apoptosis regulatory pathways and do not undergo apoptosis in these situations. Because FADD is an
essential component of receptor mediated apoptosis, a dominant-negative version (FADD-DN) is able to block apoptosis
induced by death ligands in many cell lines. While studying FADD signaling, our laboratory made the surprising discovery
that FADD-DN can induce apoptosis in normal breast epithelial cells. Because FAD%DN induces apoptosis in normal but not
cancerous breast epithelial cells, we hypothesize that FADD-DN interacts with one or more proteins expressed in breast
epithelia. Since breast tumor cells do not die in response to FADD% DN, the potential FADD- DN interacting partners are
likely to be involved in carcinogenesis. Since defects in apoptotic pathways are a prerequisite to cancer, understanding the
nature of these defects may bring about potential treatments. FADD-DN signaling presents a novel apoptotic pathway that is
fundamental in normal breast epithelia, but not breast cancer cells. Components of this pathway may identity potential
therapeutic targets that allow the reactivation of this apoptotic response in cancer cells
DTIC
Apoptosis; Cancer; Cells (Biology); Mammary Glands
20040111621 Pennsylvania Univ., Philadelphia, PA
Structural Studies of the BRCA1-Associated Human SWI/SNF Complex
Holbert, Marc A.; Apr. 2004; 12 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0630
Report No.(s): AD-A425716; No Copyright; Avail: CASI; A03, Hardcopy
Mutations in the tumor suppressor gene, BRCA1 account for 45% of families with a high incidence of breast cancer and
the majority of families with high incidences of both breast and ovarian cancers. Recent data has shown BRCA1 to be
associated to he associated with a human SW/SNF complex, saving to link breast cancer to chromatin remodeling (3). Current
evidence points to the idea that BRCA1 works through SWI/SNF; therefore a molecular understanding of the SWI/SNF
complex and other human chromatin remodeling complexes will offer insight into the biology of BRCA1. The central catalytic
AIPase submit of SWI/SNF is BRC1; the central catalytic subunit of a related human chromatin remodeling complex, NURF,
is SNF2H. initially, crystallization and Xray structural determination of the core AThase domain, in addition to the fill-length
proteins was undersaken unsuccessftilly. Initial purification and expression of a SWI/SNF tinctional core and the SNF2H
contaiaing NURF complex were also unsuccexsftil. The conserved core ATPase domain was identified in two more primitive
organisms. A recombinant homologous AThase domain was expressed, purified, and small needle-like crystals were grown.
Optimization and refinement of these initial crystals is underway to obtain Xray diffraction quality crystals for structral
determination of this homologous archacal ATPase domain.
DTIC
Cancer; Genes; Mammary Glands
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