Members of the D52 Gene family

Details Members of the D52 Gene family Members of the D52 Gene family

1999-02-17

2003-03-04

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...

C435S070100, C530S300000, C530S350000, C536S001001, C536S018700, C536S023100

Reexamination Certificate

active

06528283

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to genes expressed in breast carcinoma. In particular, the invention relates to a murine homolog and a novel isoform of a human gene expressed in breast carcinoma, and a novel member of the D52 gene family, hD54.
BACKGROUND OF THE INVENTION
D52 Gene Family
The human D52 (hD52) cDNA was initially cloned during a differential screening of a breast carcinoma cDNA library (Byrne, J. A., et al.,
Cancer Res
. 55:2896-2903 (1995)), and a hD52 cDNA (termed N8) was subsequently identified by differential display of mRNA from normal and tumor-derived lung cell lines (Chen, S -L., et al.,
Oncogene
12:741-751 (1996)). The hD52 gene was found to be overexpressed in approximately 40% of breast carcinomas, specifically in the cancer cells (Byrne, J. A., et al.,
Cancer Res
. 55:2896-2903 (1995)). Cloning of hD52 orthologues in other species has indicated that D52 proteins may participate in the calcium signaling cascade (Parente (Jr) et al.,
J. Biol. Chem
. 271:20096-20101 (1996)) and the control of cell proliferation (Proux, V., et al.,
J. Biol. Chem
. 271:30790-30797 (1996)).
Orthologues of the hD52 gene have been cloned from mouse (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)), rabbit (Parente (Jr) et al.,
J. Biol. Chem
. 271:20096-20101 (1996)), and Japanese quail (Proux, V., et al.,
J. Biol. Chem
. 271:30790-30797 (1996)), and in situ hybridization mapping has indicated that the human and mouse D52 loci are syntenically conserved, having been localized to human chromosome 8q21 (Byrne, J. A., et al.,
Cancer Res
. 55:2896-2903 (1995)), and mouse chromosome 3A1-3A2 (Byrne, J. A., et al,
Genomics
35:523-532 (1996)), respectively.
The rabbit D52 homologue CSPP28 (calcium sensitive phosphoprotein of 28 kDa) was identified as being one of several proteins known to be phosphorylated in response to cholinergic stimulation of gastric parietal cells, and it was postulated that CSPP28 may participate in the calcium signaling cascade in a variety of rabbit tissues (Parente (Jr), J. A., et al.,
J. Biol. Chem
. 271:20096-20101 (1996)). In the Japanese quail (
Cotunix coturnix japonica
), a D52 homologue R10 was identified as the cellular sequence to which retroviral sequences were joined in chimeric transcripts amplified from in vitro cultures of proliferating neuroretinal cells infected with RAY-1 (Proux, V., et al.,
J. Biol. Chem
. 271:30790-30797 (1996)). Thus, D52 may a represent signaling molecule of a calcium-sensitive signaling pathway mediating or associated with aspects of cellular proliferation. A role for both hD52 and hD53 in, or as markers of cell proliferation was also suggested by the observation that hD52 and hD53 transcript levels were decreased in HL60 and K562 leukemic cell lines, respectively, when these were cultured in the presence of 12-O-tetradecanoylphorbol-13-acetate (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)).
While the sequences of D52 proteins are highly conserved between species (Byre, J. A., et al,
Genomics
35:523-532 (1996); Parente (Jr), J A., et al.,
J. Biol. Chem
. 271:20096-20101 (1996); Proux, V., et al.,
J. Biol. Chem
. 271:30790-30797 (1996)), they exhibit insufficient homology with proteins of known function as to permit their inclusion in an existing protein family. That D52 represents the first member of a novel protein family was confirmed by the identification of the hD53 gene, whose predicted product is 52% identical/66% conserved with respect to hD52 (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)). The existence of hD53 was first indicated by several expressed sequence tags (ESTs) which showed significant levels of identity with regions of hD52 (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)). The corresponding cDNA clones were obtained, and one was used to isolate full-length cDNAs from the same breast carcinoma cDNA library used for the identification of the original hD52 cDNA (Byrne, J. A., et al.,
Cancer Res
. 55:2896-2903 (1995)). That hD53 transcripts derive from a separate gene was demonstrated by the distinct chromosomal localizations for the hD52 and hD53 loci, on human chromosomes 8q21 (Byrne, J. A., et al.,
Cancer Res
. 55:2896-2903 (1995)) and 6q22-q23 (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)), respectively.
The existence of a coiled-coil domain in D52-like molecules was predicted (Byrne, J. A., et al.,
Genomics
35:523-532 (1996); Chen, S -L., et al.,
Oncogene
12:741-751 (1996) and; Proux, V., et al.,
J. Biol. Chem
. 271:30790-30797 (1996)), which in turn suggests that their functions involve protein-protein interactions. The coiled-coil domains of D52-like proteins are highly conserved both with respect to their sequences, lengths, and locations within D52-like proteins. That a functional relationship may exist between hD52 and hD53 gene products was indicated by examples of similar regulation of hD52 and hD53 transcript levels in both breast carcinoma and leukemic cell lines, despite the fact that hD52 and hD53 transcripts derive from separate genes located on independent chromosomes (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)). This suggestion of a functional relationship between hD52 and hD53, combined with the degree of conservation between their coiled-coil domains, and the fact that hD52 and hD53 could be either co- or independently expressed, led to the hypothesis that hD52 and hD53 proteins may be capable of both homo- and heteromer formation (Byrne, J. A., et al.,
Genomics
35:523-532 (1996)).
Breast Cancer
Despite earlier detection and a lower size of the primary tumors at the time of diagnosis (Nyström, L. et al.,
Lancet
341:973-978 (1993); Fletcher, S. W. et al.,
J. Natl. Cancer Inst
. 85:1644-1656 (1993)), associated metastases remain the major cause of breast cancer mortality (Frost, P. & Levin, R.,
Lancet
339:1 458-1461 (1992)). The initial steps of transformation characterized by the malignant cell escape from normal cell cycle controls are driven by the expression of dominant oncogenes and/or the loss of tumor suppressor genes (Hunter, T. & Pines, J.,
Cell
79:573-582 (1994)).
Tumor progression can be considered as the ability of the malignant cells to leave the primary tumoral site and, after migration through lymphatic or blood vessels, to grow at a distance in host tissue and form a secondary tumor (Fidler, I. J.,
Cancer Res
. 50:6130-6138 (1990), Liotta, L. et al.,
Cell
64:327-336 (1991)). Progression to metastasis is dependent not only upon transformation but also upon the outcome of a cascade of interactions between the malignant cells and the host cells/tissues. These interactions may reflect molecular modification of synthesis and/or of activity of different gene products both in malignant and host cells. Several genes involved in the control of tumoral progression have been identified and shown to be implicated in cell adhesion, extracellular matrix degradation, immune surveillance, growth factor synthesis and/or angiogenesis (reviewed in, Hart, I. R. & Saini, A.,
Lancet
339:1453-1461 (1992); Ponta, H. et al., B.B.A. 1198:1-10 (1994); Bernstein, L. R. & Liotta, L. A.,
Curr. Opin. Oncol
. 6:106-113 (1994); Brattain, M. G. et al.,
Curr. Opin. Oncol
. 6:77-81 (1994); and Fidler, I. J. & Ellis, L. M.,
Cell
79:185-188 (1994)).
However, defining the mechanisms involved in the formation and growth of metastases is still a major challenge in breast cancer research (Rusciano, D. & Burger, M. M.,
BioEssays
14:185-194 (1992); Hoskins, K. & Weber, B. L.,
Current Opinion in Oncology
6:554-559 (1994)). The processes leading to the formation of metastases are complex (Fidler, I. J.,
Cancer Res
. 50:6130-6138 (1990); Liotta, L. et al.,
Cell
64:327-336 (1991)), and identifying the related molecular events is thus critical for the selection of optimal treatments.
SUMMARY OF THE INVENTION
The present inventors have identified a novel isoform of hD53, +5 hD53; the murine homolog of hD53, mD53; and a novel member of the D52 gene family, hD54. +5hD53, mD53, and hD54 are useful as breast ca

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