Mammary transforming protein

Details Mammary transforming protein Mammary transforming protein

1999-03-08

2002-11-19

Huff, Sheela (Department: 1642)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

C514S012200

Reexamination Certificate

active

06482922

ABSTRACT:

This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been putatively identified as mammary transforming protein. The invention also relates to inhibiting the action of such polypeptides.
Hormones from ovaries and pituitary glands are absolutely essential for the proliferation and differentiation of mammary epithelial cells (MECs), which are the predominant carcinogen-susceptible cell type in the mammary gland (Imagawa, W., Bandyopadhyay, G. K. & Nandi, S. (1990)
Endocr. Rev.
11, 494-523). Studies from several laboratories have indicated that hormones play a crucial role in chemical carcinogen-induced mammary tumorigenesis in both mouse and rat model systems (Medina, D. (1974)
J. Natl. Cancer Inst.
53, 223-226; Medina, D. (1976)
J. Nat. Cancer Inst.
57, 1185-1189; Medina, D. (1981)
Cancer Res.
41, 3819-3820; Welsch, C. W. (1987) in
Cellular and Molecular Biology of Mammary Cancer
, eds. Medina, D., Kidwell, W. Heppner, G. & Anderson, E. (Plenum, New York), pp. 163-179). Earlier studies from different laboratories have demonstrated that the nature of the carcinogen and of the tissue types determine the genotype of the lesions induced using various animal model systems. For example, in the two-stage skin carcinogenesis system, papillomas induced with the methylating agent N-methyl-N′-nitro-N-nitrosoguanidine or N-methyl-N-nitrosourea (MNU) have predominantly G→A transition mutations at codon 12 of the H-ras protooncogene (Balmain, A. & Brown, K. (1988) adv.
Cancer Res.
51, 147-182; Brown, K., Buchmann, A. & Balmain, A. (1990)
Proc. Natl. Acad. Sci. USA
87, 538-542). Similar findings have been reported in the rat mammary tumorigenesis system using MNU as a carcinogen (Sukumar, S. Notario, V., Martin-Zanca, D. & Barbacid, M. (1983)
Nature
(
London
) 306, 658-661; Zarbl, H., Sukumar, S., Arthur, A. V., Martin-Sanca, D. & Barbacid, M. (1985)
Nature
(
London
) 315, 382-385). However, skin tumors in mice and mammary tumors in mice and rats, induced with the polycyclic hydrocarbon dimethylbenz[a]anthracene, contain predominantly A→T transversion mutations at the 61st codon of the H-ras protooncogene (Zarbl, H., Sukumar, S., Arthur, A. V., Martin-Sanca, D. & Barbacid, M. (1985)
Nature
(
London
) 315, 382-385; Kumar, R., MEdina, D. & Sukumar, S. (1990)
Oncogene
5, 1271-1277; Dandekar, S., Sukumar, S., Zarbl, H., Young, L. J. T. & Cardiff, R. D. (1986)
Mol. Cell. Biol.
6,4104-4108; Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. (1986)
Nature
(
London
) 322, 78-80). A majority of thymic lymphomas induced with MNU, on the other hand, contain a G35→A35 mutation in the N-ras protooncogene (Guerrero, I., Calzada, P., Mayer, A. & Pellicer, A. (1984)
Proc. Natl. Acad. Sci. USA
81, 202-205; Guerrero, I., Villasante, A., Corces, V. & Pellicer, A. (1985)
Proc. Natl. Acad. Sci. USA
82, 7810-7814).
A defined serum-free cell culture system has been developed in which mouse MECs embedded in a three-dimensional collagen gel matrix can be grown, induced to differentiate, and be neoplastically transformed with chemical carcinogens (Guzman, R. C., Osborn, R. C., Bartley, J. C., Imagawa, W., Asch, B. B. & Nandi, S. (1987)
Cancer Res.
47, 275-280). Using this system it has been observed that the types of mammary lesions induced by carcinogens are greatly influenced by the mitogens present around the time of carcinogen treatment. It has been reported on an in vitro system, the induction of preneoplastic hyperplastic alveolar nodules (HANs) and carcinomas from MECs exposed to the direct-acting chemical carcinogen MNU in the presence of different mitogens (Miyamoto, S., Guzman, R. C., Osborn, R. C. & Nandi, S. (1988)
Proc. Natl. Acad. Sci. USA
85, 477-481). When mouse MECs were grown in the presence of the mammogenic hormones progestone and prolactin (PPRL) during MNU administration, the predominant types of lesions induced were a high incidence of HANs and carcinomas with squamous metaplasia. In contrast, when epidermal growth factor was used as a mitogen during the carcinogen treatment, only a low incidence of ductal hyperplasia was detected, although the extent of MEC proliferation between the two groups was equivalent. The genetic analysis of these lesions indicated that the activation of the protooncogene was also dependent on the mitogen used around the time of carcinogen treatment. The majority (80%) of the HANs and carcinomas induced with MNU in the presence of PPRL had an activation of the protooncogene c-Ki-ras by a specific G35→A35 point mutation at codon 12. The activation of the protooncogene was determined to be an early event in this carcinogenesis process because the activation was detected in preneoplastic lesions (Miyamoto, S., Sukumar, S., Guzman, R. C., Osborn, R. C. & Nandi, S. (1990)
Mol. Cell. Biol.
10, 1593-1599). In contrast, activation of C-Ki-ras was absent in all the ductal hyperplasias induced by MNU in the presence of the mitogen epidermal growth factor. Involvement of the same type of c-Ki-ras mutation has, however, been observed in the in vivo mouse model system where pituitary-isografted mice were injected with a single dose of MNU (Guzman, R. C., Osborn, R. C., Swanson, S. M., Sakthivel, R., Hwang, S.-I., Miyamoto, S. & Nandi, S. (1992)
Cancer Res.
52, 5732-5737). Pituitary isografts in mice raise blood levels of PPRL (Christov, K., Swanson, S. M., Guzman, R. C., Thordarson, G., Jin, E., Talamantes, F. & Nandi, S. (1993)
Carcinogenesis,
14, 2019-2025) and thereby partially mimic the in vitro PPRL culture condition. Results from another set of in vivo experiments with virgin rats also showed that a difference in experiments with virgin rats also showed that a difference in frequency of G35→A35 mutated H-ras protooncogene correlated with different stages of the estrous cycle at the time of MNU administration (Pascual, R. V., Hwang, S.-I., Swanson, S. M., Bauzon, M. K., Guzman, R. C. & Nandi, S. (1994)
Proc. Am. Assoc. Cancer Res.
35, 262).
The induction of preneoplastic and neoplastic lesions of different phenotypes by using LiCl as a mitogen during carcinogen treatment and the involvement of a transforming gene, designated MAT1, in this process, LiCl, a potent mitogen for mammary epithelial cells, has been reported, (Hori, C. & Oka, T. (1979)
Proc. Natl. Acad. Sci. USA
76, 2823-2827; Tomooka, Y., Imagawa, W., Nandi, S. & Bern, H. A. (1983)
J. Cell. Physiol.
117, 290-296). LiCl has been found to alter the phosphatidylinositol hydrolysis in MECs. Although LiCl also modules the cAMP synthesis, K
+
and Ca
2+
transport, and guanine nucleotide-binding protein synthesis in other cell types, the exact mechanism of its mitogenic effect is still unclear (Imagawa, W., Bandyopadhyay, G. K. & Nandi, S.
Endocr. Rev.
11:494-523 (1990)). This gene has been cloned and sequenced
The polypeptide of the present invention has been putatively identified as a mammary transforming protein as a result of amino acid sequence homology to mammary transforming gene (MAT1) as disclosed in Bera, T., et al., PNAS, USA, 91:9789-9793 (1994).
In accordance with one aspect of the present invention, there is provided a novel mature polypeptide, as well as biologically active and diagnostically or therapeutically useful fragments, analogs and derivatives thereof. The polypeptide of the present invention is of human origin.
In accordance with another aspect of the present invention, there are provided isolated nucleic acid molecules encoding a polypeptide of the present invention including mRNAs, cDNAs, genomic DNAs as well as analogs and biologically active and diagnostically or therapeutically useful fragments thereof.
In accordance with another aspect of the present invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressed by the DNA c

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