Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-01-11
2003-08-12
Wehbe′, Anne M. (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023500, C536S023400, C435S320100, C435S325000, C435S455000, C435S069100
Reexamination Certificate
active
06605710
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a human gene sequence that encodes the CDDF-1 polypeptide, which is involved in cell differentiation, in particular differentiation of undifferentiated or immature cells into neutrophils, monocytes/macrophages, mast cells and/or erythroid cells. The present invention further relates to assays for detecting CDDP-1 expression, vectors that express CDDP-1, methods for using CDDP-1 to induce or promote cell differentiation, and transgenic animals deficient in one or both CDDP-1 alleles. The present invention further relates to methods of gene therapy which comprise the administration of the above vectors to a human or animal.
(2) Description of Related Art
Development in higher eukaryotes proceeds by the differential, temporal, and tissue specific expression of particular genes. Among the factors which control gene expression are positive transcription factors that increase gene expression by binding to specific DNA sequences called enhancer sequences. These factors are called enhancer binding proteins. One such family of enhancer binding proteins is the CCAAT/enhancer binding protein (C/EBP) family.
The C/EBP family of transcription factors has been implicated in both the regulation of differentiation and differentiated function in myelomonocytic cells. C/EBP&agr;, C/EBP&bgr;, and C/EBP&dgr; are temporally regulated in the granulocyte-colony stimulating factor (G-CSF)-stimulated differentiation of 32D clone 3 myeloblasts into granulocytes (Scott et al., Blood 80: 1725-1735 (1992)). C/EBP&agr; is expressed at high levels early in differentiation and decreases to an undetectable level in terminally differentiated cells, while C/EBP&bgr; and C/EBP&dgr; are upregulated as the cells differentiate.
Similarly, C/EBP&bgr; is upregulated in macrophage differentiation (Natsuka et al., Blood 79: 460-466 (1992)). However, observations in primary cells and in bipotential precursor cell lines yield a somewhat different pattern of C/EBP&agr; expression (Radomska et al., Mol. Cell. Biol. 18: 4301-4314 (1998)). In these cell lines, C/EBP&agr; is first expressed when multipotential cells become committed to the myeloid lineage, then C/EBP&agr; expression is upregulated and its expression maintained during granulocytic expression, then its expression is rapidly down regulated during monocytic differentiation. Consistent with its early appearance and high level of expression in granulocyte differentiation, conditional expression of C/EBP&agr; in transfected bipotential cells induces neutrophilic differentiation and blocks monocytic differentiation (Radomska et al. ibid.). C/EBP&agr; has been shown to induce expression of the G-CSF receptor and the interleuken-6 (IL-6) receptor. Both receptors are involved in cell development.
Genetically created C/EBP&agr;-deficient mice are completely blocked in the development of neutrophils and eosinophils (Zhang et al., Proc. Natl. Acad. Sci. USA 94: 569 (1997)). While these mice no longer express the C/EBP&agr;-regulated G-CSF receptor, lack of G-CSF expression alone is not responsible for the blocked development because mice deficient in G-CSF receptor expression are still capable of producing mature neutrophils, albeit in numbers that are reduced compared to that in normal mice (Liu et al., Immunity 5: 491-501 (1996)). The IL-6 receptor is either directly or indirectly regulated by C/EBP&agr;, and IL-6 signaling is important for granulopoiesis; however, the genetically created IL-6 receptor and the G-CSF receptor deficient mice are similar to mice made deficient for only the G-CSF receptor (Zhang et al., J. Exp. Med. 188: 1173-1184 (1998)). Therefore, there must be other important C/EBP&agr; genes other than those encoding the G-CSF receptor and the IL-6 receptor.
Consistent with peak expression late in myeloid differentiation, C/EBP&bgr; and C/EBP&dgr; are effectors in the induction of proinflammatory genes responsible for LPS, IL-1, or IL-6 stimulation (Akira et al., EMBO J. 9: 1897-1906 (1990); Kinoshita et al., Proc. Natl. Acad. Sci. USA 89: 1473-1476 (1992)). The DNA binding activity of C/EBP&bgr; is increased by a post-transcriptional mechanism when cells are exposed to LPS, IL-1, or IL-6 (Akira et al. ibid.; Poli et al., Cell 63: 643-653 (1990)), and C/EBP&bgr; and C/EBP&dgr; mRNA levels can be induced by LPS, IL-1, or IL-6 (Akira et al. ibid.; Kinoshita et al. ibid.). C/EBP&bgr; expression is capable of enhancing transcription from promoters containing elements responsive to those factors (Akira et al. ibid.; Poli et al. ibid.; Chang et al., Mol. Cell. Biol. 10: 6642-6653 (1990); Descombes et al., Genes Dev. 4: 1541-1551 (1990)). Both C/EBP&bgr; and C/EBP&dgr; can transactivate a reporter gene regulated by the IL-6 promoter in transient assays (Akira et al. ibid.; Kinoshita et al. ibid.). Furthermore, the promoter regions of the genes for IL-6, IL-1&agr;, IL-1&bgr;, IL-8, tumor necrosis factor alpha (TNF&bgr;), G-CSF, macrophage inducible nitric oxide synthase (iNOS), and lysozyme (Akira et al. ibid.; Furutani et al., Nuc. Acids Res. 14: 3167-3179 (1986); Lowenstein et al., Proc. Natl. Acad. Sci. USA 90: 9730-9734 (1993); Natsuka et al., Blood 79: 460-466 (1992); Shirakawa et al., Mol. Cell. Biol. 13: 1332-1344 (1993); Zhang and Rom, Mol. Cell. Biol. 13: 3831-3837 (1993)) all contain C/EBP binding motifs. Furthermore, ectopic expression of C/EBP&agr;, C/EBP&bgr;, or C/EBP&dgr; confers LPS-inducibility of IL-6 and MCP-1 expression to cell lines that normally lack C/EBP expression (Bretz et al., Proc. Natl. Acad. Sci. USA 91: 7306-7310 (1994); Hu et al., J. Immunol. 160: 2334-2342 (1998)).
C/EBP&egr; is unique among the transcription factors of the C/EBP family because it is myeloid-specific in its expression (Williams et al., J. Biol. Chem. 273: 13493-13501 (1998); Chumakov et al., Mol. Cell. Biol. 17: 1375-1386 (1997)). In particular, C/EBP&egr; is expressed in maturing neutrophils (Chih et al., Blood 90: 2987-2994 (1997); Morosetti et al., Blood 90: 2591-2600 (1997); Yamanaka et al., Proc. Natl. Acad. Sci. USA 94: 6462-6467 (1997)). C/EBP&egr;-deficient mice fail to develop functional neutrophils and eosinophils (Yamanaka et al., Proc. Natl. Acad. Sci. USA 94: 13187-13192 (1997)) with a block later in the differentiation process than that seen in C/EBP&agr;-deficient mice. Consistent with a block later in the differentiation process, C/EBP&egr; has been found to transactivate, in cooperation with c-myb, the promoters for mim-1 and neutrophil elastase in transient expression assays (Verbeek et al., Blood 93: 3327-3337 (1999)), and to upregulate endogenous expression of a number of genes encoding proinflammatory cytokines including IL-6, MCP-1, MIP-1&agr;, and MIP-1&bgr; (Williams et al. ibid.).
C/EBP family members have also been implicated in the differentiation of the erythroid and B cell lineages. Erythropoietin upregulates expression of CHOP, a C/EBP family member that acts as a dominant negative regulator of other C/EBP family members (Coutts et al., Blood 93: 3369-3378 (1999)). Overexpression of CHOP in Rauscher cells enhanced erythropoietin and DMSO-induced differentiation, while inhibition of CHOP expression reduced CFU-E formation. C/EBP&bgr; is also upregulated in the course of erythroid differentiation. Mice deficient in C/EBP&bgr; expression are impaired in the generation of bone marrow B lymphocytes (Chen et al., Blood 90: 156-164 (1997)). These mice showed decreased expression of IL-7 by bone marrow stromal cells as well as defective IL-7 signaling. C/EBP&bgr; has also been shown to be a component of a DNA binding complex that activates the Id1 gene, a negative regulator of differentiation in pro-B cells (Saisanit and Sun, Mol. Cell. Biol. 17: 844-850 (1997)). This suggests that C/EBP&bgr; participates in blocking differentiation and promoting proliferation at the pro-B cell stage, but promotes differentiation through
Schwartz Richard C.
Tian Qiang
Board of Trustees of Michigan State University
Li Qian J
McLeod Ian C.
Wehbe′ Anne M.
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