Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-07-16
2001-11-27
Jones, W. Gary (Department: 1655)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024330, C536S023500, C536S024310, C530S350000, C435S006120
Reexamination Certificate
active
06323331
ABSTRACT:
The invention disclosed herein was made with Government support under Grant Nos. K08AI01217-01 and R29AI40246 from the National Institutes Of Health of the United States Department of Health and Human Services. Accordingly, the U.S. Government has certain rights in this invention.
BACKGROUND
Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding Sequence Listing and the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
A. Regulation of Apoptosis
1. Apoptosis is important in diverse physiologic processes; the abnormal regulation of apoptosis is important in diverse pathologic processes, including turmorigenesis.
Apoptosis is a highly conserved innate mechanism by which mammalian cells commit suicide. This mechanism allows an organism to eliminate unwanted or defective cells by an orderly process of cellular disintegration, and is characterized by certain stereotypic biochemical (e.g. endonucleosomal cleavage into 180-200 bp multimers) and morphologic features (e.g. chromatin condensation, cytoplasmic blebbing, etc.). Apoptosis plays a role in physiologic processes such as differentiation during embryogenesis, establishment of immune self-tolerance, and killing of cytotoxic immune cells, and apoptosis can be induced in response to a variety of stimuli including DNA damage, growth factor withdrawal, Ca
2+
influx, ischemia, and viral infection. The unwanted occurrence of apoptosis may play a role in neurodegenerative diseases and aging, and the diminution of apoptotic death may play a role in cancer and chemoresistance.
2. Apoptosis and the cell cycle may share common pathways.
In recent years, the concept that the cell cycle and apoptosis are inextricably linked has gained widespread support in the cell death field. Several different lines of evidence support this concept. For example, in response to different death signals, normally quiescent cells express elevated levels of cell cycle genes (Buttyan, 1991; Freeman, 1994). Oncogenes such as c-myc (Evan, et al., 1996), ras (Wyllie, et al., 1987; Tanaka, et al., 1994) and adenovirus ELA (White, 1991), that promote cell proliferation, also act as triggers of apoptosis. Loss of normal restraints at the G1 checkpoint, such as inactivation of the retinoblastoma gene product, p105Rb (Clarke, et al, 1992; Lee, et al 1992; Jacks, et al, 1992), or deregulated expression of the G1-specific E2F transcription factors (Shan, et al., 1994; Qin, et al., 1994; Wu, et al., 1994) results in uncontrolled proliferation and apoptosis. Loss of the p53 tumor suppressor gene results in resistance to certain apoptotic triggers, and p53 overexpression induces some types of apoptosis (reviewed in Evan, 1995). The morphologic features of apoptosis resemble those of mitotic catastrophe (reviewed in King and Cidlowski, 1995), and premature activation of cyclin dependent kinases is required for some forms of apoptosis (Shi, et al., 1994). Furthermore, several agents that block cell cycle progression also protect neuronal cells from apoptosis induced by withdrawal of trophic factor support (Farinelli and Greene, 1996) and T lymphocytes from apoptosis induced by T-cell receptor ligation (Boehme and Lenardo, 1993). These observations all support the notion of a link between the cell cycle and apoptosis.
3. An evolutionarily conserved set of cellular genes regulate apoptosis.
Several mammalian genes have been identified that function as either inducers (e.g. faslapo-1, bax, ICE-like cysteine proteases, p53) or repressors (e.g. bcl-2, bcl-x
s
, bcl-x
L
) of an evolutionarily conserved apoptotic death pathway. Prevailing hypotheses in the cell death field are that a family of ICE-like cysteine proteases (CED-3, ICE, Nedd-2/ICH-1, CPP32) constitute the pivotal triggers of both nematode and mammalian cell suicide program and that a family of bcl-2-related genes constitute the final downstream negative regulators of cell death. Despite the identification of several effectors and repressors of cell death, the precise molecular mechanisms underlining the action of each of these genes remains poorly defined.
4. Bcl-2, the proto-oncogene, inhibits a variety of types of apoptosis.
Bcl-2 (for B cell lymphoma 2) is the prototypic anti-apoptotic gene. It was first discovered by virtue of its involvement in the t(14:18) chromosomal translocations found in the majority of non-Hodgkin's B cell lymphomas (Tsujimoto and Croce, 1985). Bcl-2 can prevent or delay apoptosis induced by a wide variety of stimuli (reviewed in Park and Hockenbery, 1996), including growth factor deprivation, alterations in Ca
2+
, free radicals, cytoxic lymphokines, some types of viruses, radiation and most chemotherapeutic drugs. The ability of Bcl-2 to inhibit apoptosis induced by such diverse stimuli suggests that this oncoprotein controls a common final pathway involved in cell death regulation.
5. Dysregulated Bcl-2 expression occurs in a wide variety of human cancers and contributes to neoplastic cell expansion.
While the bcl-2 gene was first discovered because of its involvement in t(14:18) translocations found frequently in non-Hodgkin's lymphomas, high levels and aberrant patterns of bcl-2 gene expression have been reported in a wide variety of human cancers, including colorectal, gastric, prostate, non-small cell lung, neuroblastomas, breast and ovarian cancer (reviewed in Reed, et al., 1996). In these tumors, it is thought that Bcl-2 contributes to neoplastic cell expansion by preventing cell turnover caused by physiological cell death mechanisms. In addition to its role in the development of human tumors, high levels of Bcl-2 expression are thought to play an important role in the resistance of tumor cells to cytotoxic anticancer drugs and radiation.
6. The mechanism by which Bcl-2 inhibits apoptosis is still poorly understood.
Several potential mechanisms of action have been proposed for Bcl-2, including protection against oxidative stress (Hockenbery et al., 1993; Kane et al., 1993), regulation of intracellular Ca
2+
homeostasis (Lam, et al., 1993), antagonism of cell death proteases (e.g. ICE-like family of cysteine proteases) (Miura, et al., 1993) and other cell death effectors (e.g. bax) (Yin, et al., 1994), and association with the signal transducing proteins, R-ras and Faf-1 (Fernandez-Sarbia and Bischoff, 1993; Wang, et al., 1994). In addition, two recent reports have suggested that Bcl-2 may exert anti-apoptotic effects by delaying cell cycle progression (Mazel, et al., 1996; Borner, 1996). Despite these numerous proposed mechanisms, there is considerable contradictory evidence and no universal agreement in the cell death field as to how Bcl-2 actually works. Further elucidation of the precise mechanism(s) of action of Bcl-2 is a high research priority in the field.
7. No functional links have been identified between inhibitors of apoptosis and inhibitors of cell cycle.
According to the concept that the cell cycle is linked to apoptosis, one would predict that cellular genes that inhibit apoptosis would be functionally linked to genes that exert effects on the cell cycle. Along these lines, Bcl-2 has been shown to delay cell cycle progression (as stated above), and Bcl-2 has also been postulated to function as a nuclear “gatekeeper” that regulates nuclear access of cyclin-dependent kinases. However, to date, Bcl-2 has not been shown to directly interact with any proteins that affect the cell cycle.
8. Further investigation of the mechanism(s) underlaying the death repressor activity of Bcl-2, including the characterization of novel Bcl-2 interacting proteins, will provide new insights into apoptosis and diseases in which apoptosis plays a pathogenetic role.
Understanding how Bcl-2 inhi
Cooper & Dunham LLP
Goldberg Jeanine
Jones W. Gary
The Trustees of Columbia University in the City of New York
White John P.
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