DNA encoding a novel human inhibitor-of-apoptosis protein

Details DNA encoding a novel human inhibitor-of-apoptosis protein DNA encoding a novel human inhibitor-of-apoptosis protein

1998-07-31

2002-10-29

Caputa, Anthony C. (Department: 1642)

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, C530S300000, C530S350000, C536S001001, C536S018700, C536S022100, C536S023100, C536S023400, C536S023500

Reexamination Certificate

active

06472172

ABSTRACT:

FIELD OF THE INVENTION
This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; methods of making the polynucleotides and polypeptides, and their variants and derivatives; and uses of the polynucleotides, polypeptides, variants, and derivatives. In particular, in these and in other regards, the invention relates to novel human inhibitor-of-apoptosis polypeptides and the polynucleotides which encode these polypeptides.
BACKGROUND OF THE INVENTION
Apoptosis, also known as programmed cell death, is a genetically controlled process which plays an important role in development and in cellular and tissue homeostasis (Hengartner, M.,
Exp. Gerontol.
32: 363-374, 1997; Hoeppner et al.,
Biochem. Biophys. Acta
1242:217-220, 1996; Ellis et al.,
Annual Rev. Cell Biol.
7:663-698, 1991). Apoptosis permits the elimination of cells which either have been overproduced, developed improperly or have undergone genetic damage and represents a major host defense mechanism for limiting the replication of infective viruses. In contrast to necrotic cell death, which is usually accompanied by swelling and disruption of cellular membranes and inflammation of adjacent tissue, apoptosis is marked by cell shrinkage, blebbing, chromatin condensation, DNA fragmentation and formation of apoptotic bodies (MacLellan and Schneider,
Circ. Res.
81:137-144, 1997; Cohen, G.,
Biochem. J.
326 (Pt 1):1-16, 1997). Apoptotic cells are then phagocytosed by neighboring scavenger cells without eliciting an inflammatory response (Wu and Horvitz,
Nature
392:501-504, 1998).
Deregulation of apoptosis has been implicated in the pathogenesis of a variety of diseases. Impaired apoptosis can play a role in cancer (Pan et al.,
Cancer Surv.
29:305-327, 1997; Thompson, C.,
Science
267:1456-1462, 1995) or chronic viral infection (Clem et al.,
Science
254:1388-1390, 1991; Clem and Miller,
Mol. Cell. Biol.
14:5212-5222, 1994). Inappropriate (or premature) apoptosis may contribute to neurodegenerative disorders (Roy et al.,
Cell
80:167-178, 1995; Raff et al.,
Science
262:695-700, 1996) or acquired immunodeficiency disease (Banda, N.,
J. Exp. Med.
176:1099-1106, 1992). Premature apoptosis is also recognized as a contributing cause of myocyte loss in ischemia/repurfusion injury, myocardial infarction (MacLellan and Schneider,
Circ. Res.
81:137-144, 1997), and congestive heart failure (Feuerstein, G.,
Trends Cardiovas. Med.
7:249-255, 1997).
The presence of a novel class of apoptosis inhibitors, known as inhibitor of apoptosis proteins (IAPs) has been reported in the literature (Liston et al.,
Apoptosis
2:423-441, 1997). The first IAP was discovered in baculovirus (Crook et al.,
J. Vir.
67
:
2166
-
2174
,
1993
) and IAPs have now been reported in Drosophila, chick, mouse and human (Hay et al.,
Cell
83:1253-1262, 1995; Liston et al., supra). Five human IAPs have been identified: HIAP1, HIAP2, XIAP (X-chromosome linked IAP), NIAP (neuronal IAP) and survivin (Ambrosini et al.,
Nat. Med.
3:917-921, 1997; Duckett et al.,
Embo J.
15:2685-2694, 1996).
IAPs are a highly evolutionarily conserved family of proteins, containing a number of common structural features (domains). Among these are an N-terminal domain containing one or more repeats of a domain referred to as the BIR (baculovirus IAP repeat) domain (Liston et al., supra), and a C-terminal RING zinc finger domain. These domains are present to varying degrees within the known members of the IAP family; HIAP1 and HIAP2 contain three BIR domains and a C-terminal RING domain, while survivin contains only a single BIR domain and no RING domain.
While the physiological role of IAPs is not exactly clear, some members of the IAP family appear to play a regulatory role in apoptosis. Recombinant IAPs were found to suppress apoptosis induced by a variety of stimuli in different cell types. Drosophila IAPs (DIAP1 and DIAP2) were found to interact with a Decapentaplegic (Dpp) type I receptor, suggesting that these DIAPs may act as negative regulators of the Dpp signaling pathway, which normally leads to cell apoptosis. XIAP, HIAP1 and HIAP2 can directly inhibit specific caspases (cysteine containing aspartate specific proteases), enzymes which are involved in the pathways which control apoptosis, and thereby suppress apoptosis (Thornberry, N.,
Br. Med. Bull.
53:478-490, 1997). However, NIAP was found not to inhibit caspases, suggesting that different IAPs may have different mechanisms of action.
By helping in the regulation of programmed cell death, IAPs play an important role in the maintenance of the appropriate life cycle of the various cells of an organism. It is likely that variance from normal levels (either overabundance or deficiency) of IAPs within the cellular environment may lead to conditions in vivo which are related to various disease states.
IAPs may play a role in tumor formation. Up-regulated chicken IAP and concommitant suppression of apoptosis were found in chicken cells transformed by the oncoprotein v-rel, a member of the Rel/NF
kappa
B family (You et al.,
Mol. Cell. Biol.
17:7328-7341, 1997). Similarly, baculovirus protein p35 (a baculovirus IAP) is capable of promoting the transformation of mouse embryo fibroblasts in the presence of the insulin-like growth factor I receptor (Resnicoff et al.,
J. Biol. Chem.
273:10376-10380, 1998).
Survivin is undetectable in terminally differentiated adult tissues but expressed in all common human cancers, further suggesting that apoptosis inhibition may be a general feature of neoplasia (Ambrosini et al., supra).
Deletion mutations in human NIAP have been linked to inappropriate depletion of motor neurons associated with spinal muscular atrophy, an autosomal neurodegenerative disorder (Xu et al.,
J. Comp. Neurol.
382:247-259, 1997). In a rat ischemia model, in vivo overexpression of NIAP reduced ischemic damage in the rat hippocampus (Roy et al., supra), indicating that the presence of increased levels of IAPs could prevent the unwanted cell death characteristic of ischemia and that elevating the neuronal levels of this IAP may be useful in treating stroke.
Finally, Stellar and his colleagues were able to block retinal cell death and show significant retention of visual function in Drosophila which exhibited retinitus pigmentosa, a cause of blindness in humans, by eye-specific expression of the antiapoptotic protein p35 (Davidson and Stellar,
Nature
391:587-591, 1998).
These data suggest that antiapoptotic proteins, such as IAPs, are good candidates for use in the therapeutic intervention of diseases caused by altered apoptosis.
There is a need, therefore, for identification and characterization of proteins that influence apoptosis. In particular, there is a need to isolate and characterize additional IAPs, akin to known IAPs, which may be employed, therefore, for ameliorating or correcting dysfunctions or disease associated with inappropriate apoptosis; in cancer and chronic viral infections, where IAPs may be overproduced, as well as in neurodegenerative disorders, chronic heart failure and dysfunctional immune response, where a deficiency in IAPs may exist.
SUMMARY OF THE INVENTION
The present invention provides a polynucleotide sequence which uniquely encodes a novel human inhibitor-of-apoptosis protein. Designated HIAP3, the polypeptide is characterized by structural features common to the inhibitor-of-apoptosis protein family, such as BIR and RING domains. The polynucleotide sequence, designated in lower case, hiap3, and described in
FIG. 1
(SEQ ID NO:1) encodes the amino acid sequence, which is designated HIAP3, and is shown in
FIG. 2
(SEQ ID NO:2).
Toward these ends, and others, it is an object of the present invention to provide polypeptides, inter alia, that have been identified as a novel HIAP3 by homology between the amino acid sequence set out in
FIG. 2
(SEQ ID NO: 2) and known amino acid sequences of other IAP proteins.
It is a further object of the invention, moreover, to provide po

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