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
1998-06-17
2001-04-17
Hauda, Karen M. (Department: 1633)
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, C536S023100, C536S023500
Reexamination Certificate
active
06218144
ABSTRACT:
BACKGROUND
Segment polarity genes were originally discovered as mutations in flies that change the pattem of body segment structures. Among the genes in this class are hedgehog, patched, and costal2. The proteins encoded by these genes form a signaling pathway that regulates key events in early development, and in adult life has been implicated in carcinogenesis. The pathway has been best studied in model organisms such as flies, but it is conserved among all animals. In this pathway, the secreted signaling protein hedgehog binds to its receptor, patched, on receiving cells. Costal2 is part of the machinerythat then transduces this signal to the nucleus, resulting in changes in gene activation.
Hedgehog induces transcription of certain powerful regulatory target genes, while both patched and costal2 act in opposition to keep the target genes turned off. Other components of the pathway required for activation include the seven transmembrane protein, smoothened, the kinase fused, and cubitus inteffuptus. Experimental data suggests that hedgehog binds to patched at the cell surface, preventing patched from inactivating smoothened function. In the presence of hedgehog signal, smoothened is active, allowing it to send an activating signal to the nucleus. How hedgehog and smoothened send the activating signal to the nucleus is unknown, but genetic evidence suggests that fused and costal2 are involved. Changes in their activities are thought to allow cubitus interruptus to directly activate the transcription of hedgehog target genes.
The hedgehog signaling pathway has been implicated in several important human disease processes. For example, mutations in patched are associated with basal cell carcinomas, developmental abnormalities and brain tumors. The human homolog of cubitus interruptus, GLI, is an oncogene found in gliomas. One of the human hedgehog homologs, SHH, has also been implicated in tumorigenesis.
The characterization and identification of hedgehog signaling pathway component genes is of great interest, because of their involvement in the control of cellular differentiation and growth regulation.
RELEVANT LITERATURE
The interaction of patched (PTCH) and hedgehog is described in Chen and Struhl (1996) Cell 87: 553-563. The role of PTCH in sporadic basal cell carcinomas is described in Gailani et al. (1996) Nature Genet. 14:78-81; Hahn et al. (1996) Cell 85: 841-851; and Johnson et al. (1996) Science 272:1668-1671. Evidence that PTCH is a receptor for sonic hedgehog (SHH) is presented in Marigo et al. (1996) Nature 384:176-179; and Stone et al. (1996) Nature 384:129-134.
Cloning of SHH and IHH is described in Marigo et al. (1995) Genomics 28:44-51. The function of SHH is explored in Chiang et al. (1996) Nature 383:407-413; and Ericson et al. (1996) Cell 87:661-673.
The regulation of transcription by cubitus intemiptus is described in Von Ohlen et al. (1997) P.N.A.S. 94:2404-2409; Hepker et al. (1997) Development 124:549-558; Alexandre et al. (1996) Genes Dev. 10:2003-2013; and Dominguez et al. (1996) Science 272:1621-1625.
The first description of costal was published by Whittle (1974) Heredity 33:139. The interaction of costal2 with fused is described in Preat et al. (1993) Genetics 135:1047-1062. Genetic analysis of the region containing the Drosophila costal2 gene is found in Heitzler et al. (1993) Genetics 135:105-115.
Kinesin-like proteins are thought to be motors that bind to microtubules and use ATP to move along them like trains on tracks. Different members of the family are believed to transport different cargos. Kinesins are structurally related to myosin, even though myosin motors (which power muscle) move on actin rather than tubulin tracks, Kull et al. (1996) Nature 380:550-555. Kinesins can move toward the positive or the negative terminus of microtubules, and some act to cross-link two or more microtubules. A review of kinesins may be found in Goldstein et al. (1993) Annu. Rev. Genet. 27:319-351. The interaction between kinesins and microtubules is explored in Tucker and Goldstein (1997) J Biol Chem 272:9481-9488.
SUMMARY OF THE INVENTION
Isolated nucleotide compositions and sequences are provided for costal2 (cos2) genes. The cos2 nucleic acid compositionsfind use in identifying homologous or related genes; in producing compositionsthat modulate the expression or function of its encoded protein, Cos2; for gene therapy; mapping functional regions of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer, identification of cell type based on expression, and the like.
Cos2 encodes a kinesin-related protein that accumulates preferentially in cells capable of responding to Hh. Cos2 is cytoplasmic and binds both to microtubules and to the gene products of fused (fu), and cubitus interruptus (Ci), suggesting that Cos2 directly controls the activity of Ci. Cos2 plays a novel role for kinesin-related proteins in regulating signal transduction. The cos2 protein is useful as an immunogen for producing specific antibodies, in screening for biologically active agents that act in the hedgehog signaling pathway and for therapeutic and prophylactic purposes.
REFERENCES:
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Marigo, Valeria, et al., “Biochemical Evidence that Patched Is The Hedgehog Receptor,”Nature(Nov. 14, 1996) vol. 384:176-179.
Marigo, Valeria, et al., “Cloning, Expression, And Chromosomal Location Of SHH And IHH: Two Human Homologues Of The Drosophila Segment Polarity Gene Hedgehog,”Genomics(1995) vol. 28:44-51.
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Scott Matthew P.
Sisson John C.
Borden Paula A.
Bozicevic Field & Francis LLP
Chen Shin-Lin
Hauda Karen M.
Sherwood Pamela J.
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