Genes and proteins encoded thereby

Details Genes and proteins encoded thereby Genes and proteins encoded thereby

2000-09-14

2002-08-27

Carlson, Karen Cochrane (Department: 1653)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S252300, C435S320100, C536S023100, C530S350000

Reexamination Certificate

active

06440732

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the field of medicine, and relates specifically to methods and compositions for modulating cell growth and death, including cell formation of tissues, using novel proteins, variants of these proteins and nucleic acids encoding them.
BACKGROUND OF THE INVENTION
The integrity of the genome is of prime importance to a dividing cell. In response to DNA damage, eukaryotic cells rely upon a complex system of controls to delay cell-cycle progression. The normal eukaryotic cell-cycle is divided into 4 phases (sequentially G1, S, G2, M) which correlate with distinct cell morphology and biochemical activity. Cells withdrawn from the cell-cycle are said to be in G0, or non-cycling state. When cells within the cell-cycle are actively replicating, duplication of DNA occurs in the S phase, and active division of the cell occurs in M phase. See generally Benjamin Lewin,
GENES VI
(Oxford University Press, Oxford, GB, Chapter 36, 1997). DNA is organized in the eukaryotic cell into successively higher levels of order that result in the formation of chromosomes. Non-sex chromosomes are normally present in pairs, and during cell division, the DNA of each chromosome replicates resulting in paired chromatids. (See generally Benjamin Lewin,
GENES VI
(Oxford University Press, Oxford, GB, Chapter 5, 1997).
The eukaryotic cell cycle is tightly regulated by intrinsic mechanisms that ensure ordered progression through its various phases and surveillance mechanisms that prevent cycling in the presence of aberrant or incompletely assembled structures. These negative regulatory surveillance mechanisms have been termed checkpoints (Hartwell and Weinert, 1989, “Checkpoints: controls that ensure the order of cell cycle events”
Science,
246: 629-634). The mitotic checkpoint prevents cells from undergoing mitosis until all chromosomes have been attached to the mitotic spindle whereas the DNA structure checkpoint, which can be subdivided into the replication and DNA damage checkpoint, result in arrests at various points in the cell cycle in the presence of DNA damage or incompletely replicated DNA (Elledge, 1996, “Cell cycle checkpoints: preventing an identity crisis.”
Science,
274: 1664-1672). These arrests are believed to allow time for replication to be completed or DNA repair to take place. Cell cycling in the presence of DNA damage, incompletely replicated DNA or improper mitotic spindle assembly can lead to genomic instability, an early step in tumorigenesis. Defective checkpoint mechanisms, resulting from inactivation of the p53, ATM, and Bub1 checkpoint gene products have been implicated in several human cancers.
Checkpoint delays provide time for repair of damaged DNA prior to its replication in S-phase and prior to segregation of chromatids in M-phase (Hartwell and Weinert, 1989, supra.). In many cases the DNA-damage response pathways cause arrest by inhibiting the activity of the cyclin-dependent kinases (Elledge, 1997, supra.). In human cells the DNA-damage induced G2 delay is largely dependent on inhibitory phosphorylation of Cdc2 (Blasina et al., 1997, “The role of inhibitory phosphorylation of cdc2 following DNA replication block and radiation induced damage in Human cells.”
Mol. Biol. Cell
8: 1013-1023; Jin et al., 1997, “Role of inhibiting cdc2 phosphorylation in radiation-induced G2 arrest in human cells.”
J. Cell Biol.
134: 963-970), and is therefore likely to result from a change in the activity of the opposing kinases and phosphatases that act on Cdc2. However, evidence that the activity of these enzymes is substantially altered in response to DNA damage is lacking (Poon et al., 1997, “The role of cdc2 feedback loop control in the DNA damage checkpoint in mammalian cells.”
Cancer Res.,
57: 5168-5178).
Three distinct Cdc25 proteins are expressed in human cells. Cdc25A is specifically required for the G1-S transition (Hoffmann et al., 1994, “Activation of the phosphatase activity of human CDC25A by a cdk2-cyclin E dependent phosphorylation at the G-1/S transition.”
EMBO J.,
13: 4302-4310; Jinno et al., 1994, “Cdc25A is a novel phosphatase functioning early in the cell cycle”
EMBO J.,
13: 1549-1556), whereas Cdc25B and Cdc25C are required for the G2-M transition (Gabrielli et al., 1996, “Cytoplasmic accumulation of cdc25B phosphatase in mitosis triggers centrosomal microtubule mucleation in HeLa cells”
J. Cell Sci.,
109(5): 1081-1093; Galaktionov et al., 1991, “Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins”
Cell,
67: 1181-1194; Millar et al., 1991, “p55CDC25 is a nuclear protein required for the initiation of mitosis in human cells”
Proc. Natl. Acad. Sci. USA
88: 10500-10504; Nishijima et al., 1997
, J. Cell Biol.,
138: 1105-1116). The exact contribution of Cdc25B and Cdc25C to M-phase progression is not known.
Much of our current knowledge about checkpoint control has been obtained from studies using budding (
Saccharomyces cerevisiae
) and fission (
Schizosaccharomyces pombe
) yeast. A number of reviews of our current understanding of cell cycle checkpoint in yeast and higher eukaryotes have recently been published (Hartwell & Kastan, 1994, “Cell cycle control and Cancer”
Science,
266: 1821-1828; Murray, 1994, “Cell cycle checkpoints”
Current Opinions in Cell Biology,
6: 872-876; Elledge, 1996, supra; Kaufmann & Paules, 1996, “DNA damage and cell cycle checkpoints”
FASEB J.,
10: 238-247). In the fission yeast six gene products, rad
+
, rad3
+
, rad9
+
, rad17
+
, rad26
+
, and hus1
+
have been identified as components of both the DNA-damage dependent and DNA-replication dependent checkpoint pathways. In addition cds1
+
has been identified as being required for the DNA-replication dependent checkpoint and rad27
+
/chk1
+
has been identified as required for the DNA-damage dependent checkpoint in yeast.
Several of these genes have structural homologues in the budding yeast. Further conservation across eukaryotes has recently been suggested with the cloning of several human homologues of
S. pombe
checkpoint genes, including two related to
S. pombe
rad3
+
: ATM (ataxia telangiectasia mutated) (Savitsky et al., 1995, “A single ataxia telangiectasia gene with a product similar to PI-3 kinase”
Science,
268: 1749-1753) and ATR (ataxia telangiectasia and rad3
+
related)(Bentley et al, 1996, “The Schizosaccharomyces pombe rad3 checkpoint genes”
EMBO J.,
15: 6641-6651; Cimprich et al., “cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein” 1996
, Proc. Natl. Acad. Sci. USA,
93: 2850-2855); and human homologues of
S. pombe
rad9+, Hrad9 (Lieberman et al., 1996, “A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene”
Proc. Natl. Acad. Sci. USA,
93: 13890-13895), Hrad1 (Parker et al., 1998, “Identification of a human homologue of the
Schizosaccharomyces pombe
rad17+ checkpoint gene”
J. Biol. Chem.
273:18340-18346; Freire et al., 1998, “Human and mouse homologs of
Schizosaccharomyces pombe
rad1(+) and
Saccharomyces cerevisia
RAD17: linkage to checkpoint control and mammalian meiosis”
Genes Dev.
12:2560-2573; Udell et al., 1998, “Hrad1 and Mrad1 encode mammalian homologues of the fission yeast rad1(+) cell cycle checkpoint control gene”
Nucleic Acids Res.
26:2971-3976), Hrad17 (Parker et al., 1998, supra), Hhus1 (Kostrub et al., 1998, “Hus1p, a conserved fission yeast checkpoint protein, interacts with Rad1p and is phosphorylated in response to DNA damage”
EMBO J.
17:2055-2066), Hchk1 (Sanchez et al., 1997, “Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25”
Science
277:1497-1501) and Hcds1 (Matusoka et al., 1998, “Linkage of ATM to cell cycle regulation by the Chk2 protein kinase”
Science
282(5395): 1893-1897; Blasina et al., 1999, “A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase”
Cur

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