Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2000-12-14
2003-06-17
Priebe, Scott D. (Department: 1635)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S455000, C435S243000, C435S410000, C435S348000, C435S352000, C435S358000, C435S468000, C435S471000, C435S252300, C435S254110, C536S023100, C536S023500
Reexamination Certificate
active
06579701
ABSTRACT:
BACKGROUND OF THE INVENTION
Apoptosis, also known as programmed cell death, is important in embryonic development, metamorphosis, tissue renewal, and hormone-induced tissue atrophy, and is implicated in many pathological conditions. In multicellular organisms, apoptosis ensures the elimination of superfluous cells including those that are generated in excess, have already completed their specific functions or are harmful to the whole organism. In reproductive tissues that are characterized by cyclic functional changes, massive cell death occurs under the control of hormonal signals. A growing body of evidence suggests that the intracellular “death program” activated during apoptosis is similar in different cell types and conserved during evolution (Thompson, Science (1995) 267:1456-1462; Steller, Science (1995) 267:1445-1449). Apoptosis is induced by events such as growth factor withdrawal and toxins, and is controlled by inhibitory or “anti-apoptotic” regulators, and by “pro-apoptotic” regulators that block the protective effect of inhibitors (Vaux, Curr. Biol. (1993) 3:877-878; White, Genes Dev. (1996) 10:2859-2869). Many viruses have anti-apoptosis genes that prevent their target-cells from entering into defensive apoptosis.
Apoptosis involves two essential steps: a “decision” step and an “execution” step. The Bcl-2 family of proteins, which comprises several anti- and pro-apoptotic members, is implicated in a cell's decision whether to undergo apoptosis (Kroemer, Nat. Med. (1997) 3:614-620). The execution step is mediated by the activation of caspases and cysteine proteases that induce cell death via the proteolytic cleavage of substrates vital for cellular homeostasis (Miura et al., Cell (1993) 75:653-660; Yuan et al., Cell (1993) 75:641-652). Bcl-2-related proteins act upstream from caspases in the cell death pathway (Hengartner and Horvitz, Cell (1994) 76:665-676). Recent studies demonstrated that a
C. elegans
gene, ced-4, which is homologous to the mammalian gene Apaf-1, can bridge between Bcl-2/ced-9 family members and caspases (Chinnaiyan et al., Science (1997) 275:1122-1126; Zou et al., (1997) Cell 90:405-413).
The regulation of apoptosis depends both on stimulatory and inhibitory pathways. One class of inhibitory proteins comprises the Inhibitor of Apoptosis Proteins, or IAPs. These proteins were initially discovered in baculoviruses, which utilize IAPs to prevent their target cell from entering into defensive apoptosis. IAPs were subsequently found to exist in many multicellular organisms including flies, mice, and humans (for review see Deveraux and Reed, Genes & Dev. (1999) 13:239-252.). IAPs contain from one to three repeats of an amino acid domain called a baculovirus inhibitor of apoptosis repeat, abbreviated “BIR”. The BIR motif comprises about 70 residues arranged in tandem repeats separated by a linker of variable length. These repeats are intrinsic to the inhibitory activity of these proteins, and have been shown to inhibit caspases. BIRs also interact with and block other upstream pro-apoptotic proteins.
Growth factor receptors activate intracellular phosphorylation cascades that lead to changes in gene expression. The genes that growth factors induce fall into two classes: (1) early response genes that are induced immediately after growth factor treatment and that do not require protein synthesis for their induction, and (2) delayed response genes that require protein synthesis for induction (Almendral et al., Mol Cell Biol. (1988) 8:2140-2148; Naeve et al., Curr Opin Cell Biol. (1991) 3:261-268). Early response genes are not transcribed in resting cells, but are induced to high levels when growth factors are added to the medium. The best studied early response genes are the myc, fos and jun protooncogenes, all of which encode gene regulatory proteins that cause uncontrolled proliferation if overexpressed or hyperactivated. Thus understanding the signaling pathways of growth factor response proteins may lead to targets for cancer therapeutics.
The ADAM family of transmembrane proteins (ADAMs) contain disintegrin and metalloprotease domains and, therefore, potentially have both cell adhesion and protease activities. Members of the ADAM family have been implicated in many biological processes involving cell-cell and cell-matrix interactions, such as fertilization, processing of ectodomain proteins such as TNF, neurogenesis, muscle fusion, and Notch-mediated signaling (Schlondorff and Blobel, J Cell Sci (1999) 112(Pt 21):3603-3617; Wolfsberg et al.; J. Cell Biol. (1995) 131: 275-278).
ADAMs share all or some of the following domain structures: a signal peptide, a propeptide, a metalloproteinase domain, a disintegrin domain, a cysteine-rich domain, an epidermal growth factor (EGF)-like domain, a transmembrane region, and a cytoplasmic tail. ADAMs are widely distributed in many organs, tissues, and cells, such as brain, testis, epididymis, ovary, breast, placenta, liver, heart, lung, bone, and muscle. These proteins are capable of four potential functions: proteolysis, adhesion, fusion, and intracellular signaling.
The only known member of ADAMs in invertebrates is the Drosophila Kuzbanian (Qi et al., Science. (1999) 283(5398):91-94). The ADAM ligand/enzyme proteins may play a role in other developmental system in Drosophila where integrins are known to be important, such as determination of synaptic specificity (Beumer et al., Development (1999)126(24):5833-5846), wing morphogenesis (Brabant et al., Ann N Y Acad Sci (1998) 857:99-109), midgut cell migration (Martin-Bermudo et al., Development (1999) 126(22):5161-9), axon guidance (Hoang and Chiba, J Neurosci (1998) 18(19):7847-7855, and olfactory memory (Connolly and Tully, Curr Biol (1998) 8(11):R386-389).
The c-Myb and v-Myb proteins are transcription factors that regulate cell proliferation and differentiation (Ness, Oncogene (1999) 18(19):3039-3046). Both Myb proteins have been shown to interact with a number of cellular proteins, some of which are transcription factors that cooperate to activate specific promoters, while others regulate the transcriptional activity of Myb (Ness, supra). Transcription factors such as myb have been found to be oncogenic either when functionally altered through fusion with other proteins or through deregulated expression (Introna and Golay, Leukemia (1999) 13(9):1301-1306). In addition, clinical trials for the treatment of human leukemias by antisense-mediated disruption of the myb gene are underway (Gewirtz, Oncogene (1999) May 18(19):3056-3062). Thus, disruption of myb function, possibly by small molecule inhibitors of protein-protein interactions, may be an effective treatment for human malignancies. Hematopoietic tumors in both humans and mice frequently up-regulate expression of the c-myb gene, but it is unclear whether this is a cause or a consequence of the leukemic state (Weston, Oncogene (1999) 18(19):3034-3038). However, support for the idea that myb may be a target for cancer treatment is found in the recent discovery that c-Myb levels in colon tumor cells may lead to persistent bcl-2 expression, thus protecting tumor cells from programmed cell death (Thompson et al., Cancer Res. (1998) 58(22):5168-5175). This finding implies that interference with increased c-Myb levels may promote apoptosis, a natural defense against renegade cancer cells.
Phosphatidylinositol, a component of eukaryotic cell membranes, is unique among phospholipids in that its head group can be phosphorylated at multiple free hydroxyls. Several phosphorylated derivatives of phosphatidylinositol, collectively termed phosphoinositides, have been identified in eukaryotic cells from yeast to mammals. Phosphoinositides are involved in the regulation of diverse cellular processes, including proliferation, survival, cytoskeletal organization, vesicle trafficking, DNA damage response, glucose transport, and platelet function. The enzymes that phosphorylate phosphatidylinositol and its derivatives are termed phosphoinositide kinases. Phosphatidylinositol (PI)-3 kinase is an enzyme that phospho
Keegan Kevin Patrick
Stout Thomas J.
Brunelle Jan P.
Exelixis Inc.
Priebe Scott D.
Shayesteh Laleh
Whiteman Brian
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