Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-30
2004-10-05
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S345000, C514S293000, C514S292000, C514S187000, C514S418000, C514S266400, C514S346000, C514S445000, C514S369000, C514S414000, C514S184000, C514S342000, C514S363000, C514S228200, C514S234500, C514S253030, C514S235200, C514S254090, C424S134100, C424S145100
Reexamination Certificate
active
06800649
ABSTRACT:
BACKGROUND OF THE INVENTION
The protooncogene c-jun is the cellular counterpart of the v-jun. oncogene of avian sarcoma virus 17. C-jun expression is activated in response to a diverse set of DNA-damaging agents including ara-C, UV radiation, topoisomerase II inhibitors, alkylating agents, and ionizing radiation. As an immediate early response gene that is rapidly induced by pleiotropic signals, c-jun may have important regulatory functions for cell cycle progression, proliferation, and survival. See Ryder, K., Lau, L. F., and Nathans, D. “A gene activated by i:3 growth factors is related to the oncogene v-jun,”
Proc Natl Acad Sci USA.
85: 1487-1491, 1988; Schutte, J., Viallet, J., Nau, M., Segal, S., Fedorko, J., and Minna, J. “jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun,
Cell.
59: 987-997, 1989; Neuberg, M., Adamkiewicz, J., Hunter, J. B., and Mueller, R. “A fos protein containing the Jun leucine zipper forms a homodimer which binds to the AP-1 binding site,”
Nature.
341: 589-590, 1989; Mitchell, P. J. and Tjian, R. “Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins,”
Science.
245: 371-378, 1989; Bohmann, D., Bos, T. J., Admon, T., Nishimura, R., Vogt, P. K., and Tijian, R. “Human protooncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1,
” Science.
238: 1386-1392, 1988; Kharbanda, S. M., Sherman, M. L., and Kufe, D. W. “Transcriptional regulation of c-jun gene expression by arabinofuranosylcytosine in human myeloid leukemia cells,”
J Clin Invest.
86: 1517-1523, 1990; Rosette, C. and Karin, M. “Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors,” i Science. 274: 1194-7, 1996; Rubin, E., Kharbanda, S., Gunji, H., and Kufe, D. “Activation of the c-jun protooncogene in human myleloid leukemia cells treated with etoposide,”
Molecular Pharmacology.
39: 697-701, 1991; Dosch, J. and Kaina, B. “Induction of c-fos, c-jun, junB and junD mRNA and AP-1 by alkylating mutagens in cells deficient and proficient for the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) and its relationship to cell death, mutation induction and chromosomal instability,”
Oncogene.
13: 1927-35, 1996; Chae, H. P., Jarvis, L. J., and Uckun, F. M. “Role of tyrosine phosphorylation in radiation-induced activation of c-jun protooncogene in human lymphohematopoietic precursor cells,”
Cancer Res.
53: 447-51, 1993; and Karin, M., Liu, Z.-G., and Zandi, E. “AP-1 function and regulation,”
Current Opinion in Cell Biology.
9: 240-246, 1997.
C-jun encodes the nuclear DNA-binding protein, JUN, that contains a leucine-zipper region involved in homo- and heterodimerization. JUN protein dimerizes with another JUN protein or the product of c-fos gene and forms the activating protein-1 (AP-1) transcription factor. JUN-JUN homodimers and JUN-FOS heterodimers preferentially bind to a specific heptameric consensus sequence found in the promoter region of multiple growth regulatory genes. Alterations of c-jun protooncogene expression can therefore modulate the transcription of several growth-regulators affecting cell proliferation and differentiation. See Ryder, K., Lau, L. F., and Nathans, D. “A gene activated by growth factors is related to the oncogene v-jun,”
Proc Natl Acad Sci USA.
85: 1487-1491, 1988; Neuberg, M., Adamkicwicz, J. Hunter, J. B., and Mueller, R. “A fos protein containing the Jun leucine zipper forms a homodimer which binds to the AP-1 binding site,”
Nature.
341: 589-590, 1989; Karin, M., Liu, Z.-G., and Zandi, E. “AP-1 function and regulation,”
Current Opinion in Cell Biology.
9: 240-246, 1997; Angel, P., Allegretto, E. A., Okino, S. T., Hattori, K., Boyle, W. J., Hunter, T., and Karin, M. “Oncogene jun encodes a sequence-specific trans-activator similar to AP-1,
” Nature.
332: 166-170, 1988; and Musti, A. M., Treier, M., and Bohmann, D. “Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases,”
Science.
275: 400-402, 1997.
C-jun plays a pivotal role in Ras-induced transformation and has also been implicated as a regulator of apoptosis when de novo protein synthesis is required. C-jun induction is required for ceramide-induced apoptosis and stress-induced apoptosis after UV exposure or other forms of DNA damage. This induction is thought to be triggered by activation of JUN-N-terminal kinases (JNKs) (also known as stress-activated protein kinases) which leads to enhanced c-jun transcription by phosphorylation of JUN at sites that increases its ability to activate transcription. Ectopic expression of a dominant-negative c-jun mutant lacking the N terminus or a dominant-negative JNK kinase abolishes stress-induced apoptosis. See Karin, M., Liu, Z.-G., and Zandi, E. “AP-1 function and regulation,”
Current Opinion in Cell Biology.
9: 240-246, 1997; Collotta, F., Polentarutti, N., and Mantovani, A. “Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines,”
J. Biol. Chem.
267: 18278-18283, 1992; Ham, J., Babij, C., Whitfield, J., Pfarr, C. M., Lallemand, D., Yaniv, M., and Rubin, L. L. “A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death,”
Neuron.
14: 927-939, 1995; Verheij, M., Bose, R., Lin, X. H., Yao, B., Jarvis, W. D., Grant, S., Birrer, K M. J., Szabo, E., Zon, L. I., Kyriakis, J. M., Haimovitz F A., Fuks, Z., and Kolesnick, R. N. “Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis,”
Nature.
380: 75-9, 1996; Hibi, M., Lin, A., Smeal, T., Minden, A., and Karin, M. “Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain,”
Genes Dev.
7: 2135-48, 1993; Derijard, B., Hibi, M., Wu, I. H., Barrett, T., Su, B., Deng, T., Karin, M., and Davis, R. J. “JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain,”
Cell.
76: 1025-37, 1994; and Chen, Y. R., Wang, X., Templeton, D., Davis, R. J., and Tan, T. H. “The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation,”
J Biol Chem.
271: 31929-36, 1996.
Protein tyrosine kinases (PTK) play important roles in the initiation and maintenance of biochemical signal transduction cascades that affect proliferation and survival of B-lineage lymphoid cells. Oxidative stress has been shown to activate BTK, SYK, and Src family PTK. It is known that PTK activation precedes and mandates radiation-induced activation of c-jun protooncogene expression in human B-lineage lymphoid cells (Chae, H. P., Jarvis, L. J., and Uckun, F. M. Cancer Res. 53: 447-51, 1993). However, the identity of the PTK responsible for radiation-induced c-jun activation is not yet known. See Uckun, F. M., Waddick, K. G., Mahajan, S., Jun, X., Takata, M., Bolen, J., and Kurosaki, T. “BTK as a mediator of radiation-induced apoptosis in DT-40 lymphorna B cells,”
Science.
273: 1096-100, 1996; Kurosaki, T. “Molecular mechanisms in B cell antigen receptor signaling,”
Curr Opin Immunol.
9: 309-18, 1997; Uckun F. M., Evans W. E., Forsyth C. J., Waddick K. G., T-Ahlgren L., Chelstrom L. M., Burkhardt A., Bolen J., Myers D. E. “Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases.”
Science
267:886-891, 1995; Myers D. E., Jun X., Waddick K. G., Forsyth C., Chelstrom L. M., Gunther R. L., Turner N. E., Bolen J., Uckun F. M. “Membrane-associated CD19-LYN complex is an endogenous p53-independent and bcl-2-independent regulator of apoptosis in human B-lineage lymphoma cells.”
Proc Nat'l Acad Sci USA
92: 9575-9579, 1995; Tuel Ahlgren, L., Jun, X., Waddick, K. G., Jin, J., Bolen, J., and Uckun, F. M. “Role of tyrosine phosphorylation in radiation-induced cell cycle-arrest of leukemic B
Low Christopher S. F.
Parker Hughes Institute
Robinson Hope A.
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