Prolactin regulatory element binding protein and uses thereof

Details Prolactin regulatory element binding protein and uses thereof Prolactin regulatory element binding protein and uses thereof

2000-03-23

2003-07-01

McGarry, Sean (Department: 1635)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S006120, C435S091100, C435S325000, C435S455000, C536S023100

Reexamination Certificate

active

06586581

ABSTRACT:

1. INTRODUCTION
The present invention relates to isolated nucleic acids encoding Prolactin Regulatory Element Binding (PREB) protein and recombinant proteins encoded thereby. The nucleic acid sequences are useful in the production of recombinant PREB, as probes, and in the control of prolactin gene expression. In particular embodiments of the invention, PREB nucleic acid sequences are used to detect transcripts of the gene in astrocytomas. The PREB protein is associated with the kinase-mediated hormonal regulation of prolactin gene expression, and may be used as a trans-acting control of transcription.
2. BACKGROUND OF THE INVENTION
2.1. FUNCTION OF THE PROLACTIN HORMONE
Prolactin (PRL) is an anterior pituitary hormone that is part of a family of hormones. Prolactin was discovered in 1928 based on the ability of pituitary extracts to cause lactation in pseudo-pregnant rabbits. Cooke, N. E., and Leibhaber, S. A., 1995
, Vitamins and Hornones
50:385-459. Accumulated data now suggest a very broad spectrum of roles for PRL. PRL is linked to over three-hundred separate actions in vertebrates including effects on water and salt balance, growth and development, metabolism, brain behavior, reproduction, and immune regulation and protection. Bole-Feysot C. et al.,1998
, Endocr. Rev
. June; 19(3):225-268. Additionally, a number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL. Bole-Feysot C. et al., 1998
, Endocr. Rev. June
; 19(3):225-268.
Studies have shown that female transgenic mice over-expressing the rat PRL gene all develop mammary carcinomas at 11-15 months of age and male transgenic mice over-expressing PRL develop dramatic enlargement of the prostate gland. Wennbo H. et al., 1997
, J Clin. Invest
. December 1; 100 (11):2744-2751. The effect of PRL on cell proliferation was studied in a mouse mammary tumor cell line. The results of the study indicated that PRL antiserum is able to inhibit cell growth by 70% suggesting that PRL may be acting as a local growth factor that stimulates the proliferation of mammary tumors. Mersho, J. et al., 1995,
Endocrinology
. August; 136(8):3619-3623. Similarly, human breast cancer cells synthesize and secrete biologically active PRL and there is evidence to support that PRL may be involved in an autocrine/paracrine stimulatory loop within breast tissues that may play a role in the pathogenesis of breast cancer. Clevenger C. V. et al., 1995
, Am. J Pathol
. March; 146(3):695-705.
In addition, PRL is produced by leukocytes and fibroblasts and animal model studies suggest that increased levels of serum PRL may influence the course of arthritis, lupus, and autoimmune type I diabetes, indicating that PRL may play a role in autoimmune diseases and the regulation of immune responses. Neidhart, M., 1998
, Proc. Soc. Exp. Biol. Med
. April; 217(4):408-419. Ferrag, F. et al., 1997
, Cytokines Cell Mol Ther. September;
3(3):197-213. There an important aspect of therapeutic approaches with respect to these diseases is the understanding of the regulation of PRL expression.
2.2. TISSUE SPECIFIC EXPRESSION OF PROLACTIN
The prolactin gene appears to function as an important element in tissue-specific and developmentally regulated gene expression. Cooke, N. E. and Liebhaber, S. A., 1995
, Vitamins and Hormones
50:385-459. Prolactin is expressed in a cell-type specific fashion in pituitary lactotropic cells. Cooke, N. E. and Liebhaber, S. A., 1995
, Vitamins and Hormones
50:385-459. In addition, prolactin expression has been found in human endometrial cells, human breast tissue, human mammary cell lines, human ovaries, human immune system cells and tissues (thymus, spleen, tonsil, lymph node, lymphocytes, and lymphoid tumors), epithelial cells, vascular endothelial cells, hypothalamic cells, and in human decidua-chorion. Tanaka, S. et al., 1996
, Eur. J Endocrinol
. 135(2):177-183; Shaw-Bruha, C. M., 1997
, Breast Cancer Res. Treat
. 44(3):243-253; Schwarzler, P. et al., 1997
, Fertil. Steril
. 68(4):696-701; Wu, H. et al., 1996
, Endocrinology
137(1):349-353; Clapp, C. et al., 1994
, Proc. Natl. Acad. Sci. USA
91(22):10384-10388; Clements, J., 1983
, Endocrinology
112(3):1133-1134. Among human tissues which do not express prolactin are lung and kidney as well as many others. Schwarzler, P. et al., 1997
, Fertil. Steril
68(4):696-701. Although it has been shown that prolactin is expressed in a tissue dependent manner, it is not clear which transcription factors are responsible. While Pit-1, the POU homeo-domain transcription factor (a variant of the helix-turn-helix type transcription factor), gene expression has been shown to follow levels of prolactin expression, Pit-1 is expressed in 3 cell types of the pituitary (thyrotropic cells, lactotropic cells, somoatotropic cells, somatolactortropic cells) while prolactin is primarily expressed in lactotropic cells. Crenshaw, E. B. et al., 1989
, Genes Dev
. 3(7):959-972. The mechanism of tissue specific expression of prolactin is still being investigated.
2.3. PRL REGULATION
Transcription factors are proteins that bind to regulatory elements in genes and have a critical role in gene regulation and protein expression during development, cellular growth and differentiation. Transcription factors generally can be categorized into four major groups according to the motif in their DNA-binding domains which include (1) the helix-turn-helix group, (2) the zinc finger group, (3) the leucine zipper group, and (4) the helix-loop-helix group. Lloyd, R. V. and Osamura, R. Y., 1997
, Microsc. Res. Tech
. 3 9(2):168-181.
The prolactin promoter contains multiple binding sites implicated in basal PRL expression and in kinase-mediated hormonal regulation of the gene. The pituitary-specific transcription factor Pit-1 has been shown to play an important role in the expression by the pituitary of the prolactin gene both in development and in the mature organism. Iverson, R. A. et al., 1990
, Mol. Endocrinol
. 4:1564-1571. Okimura, Y. et al., 1994
, Mol. Endocrinol
. 8:1559-1565. Although Pit-1 binds to many of the binding sites in the PRL promoter, it does not appear to be responsible for kinase-mediated hormonal regulation of PRL. Fischberg, D. J. et al., 1994, Mol. Endocrinol. 8:1566-1573; Okimura, Y. et al., 1994, Mol. Endocrinol. 8:1559-1565; Howard, P. W. and Maurer, R. A., 1994
, J Biol. Chem
. 269:28662-28669. This suggests that there are factors other than Pit-1 that are responsible for the regulation of PRL gene expression.
Oct-1 and TEF are two other transcription factors which can bind to the promoter of the PRL gene. Voss, J. W. et al., 1991
, Genes Dev
. 5:1309-1320; Drolet, D. W. et al., 1991
, Genes Dev
. 5:1739-1753. Studies show that Oct-1 is unlikely to be involved in the kinase-mediated transcription of the prolactin gene since protein kinase A (PKA)-mediated phosphorylation of Oct-1 decreases its DNA binding activity. Segil, N. et al., 1991
, Science
254
:
1814
-
1816
. Additionally, TEF is not likely to be involved in the kinase-mediated transcription of the prolactin gene since its mode of action is apparently limited to thyrotroph development. Voss, J. W. et al., 1991
, Genes Dev
. 5:1309-1320.
Mutations in the Pit1 gene, observed in the naturally occurring Snell (dw) and Jackson (dwJ) mutant mice, result in a murine phenotype of severe growth retardation and a remarkably hypoplastic pituitary gland, due to a developmental failure of the three anterior pituitary cell types that specifically express the hormones regulated by Pit1. See Li et al.,
Nature
347:528-533 (1990). Mutations in the human homologue of Pit1 have also been shown to be responsible for deficiencies of these three pituitary hormones, and to result in a human phenotype of growth abnormalities, severe mental retardation, failure of lactation, congenital hypoparathyroidism, facial dysmorphism and hypoplastic pituitary. See Radovick et al,
Science
57:1115-1118 (1992); Tatsumi et al.,
Nat. Genet
. 1:56-58 (1992); de Zegher et al,

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