G-protein coupled receptor—encoding nucleic acids

Details G-protein coupled receptor—encoding nucleic acids G-protein coupled receptor—encoding nucleic acids

2000-04-20

2003-09-16

Eyler, Yvonne (Department: 1646)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S252300, C435S254110, C435S254200, C435S320100, C435S069100, C536S063000, C530S350000

Reexamination Certificate

active

06620615

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally to nucleic acids and polypeptides and more particularly to nucleic acids expressed in different levels in diseased versus non-diseased tissue.
BACKGROUND OF THE INVENTION
G-Protein Coupled Receptors (GPCRs) have been described in a number of species. These receptors typically share a seven transmembrane domain structure that is also observed in neurotransmitter and hormone receptors. These structural similarities may reflect functional similarities in recognition and G-protein-mediated transduction of extracellular signals.
The human GPCR genes are reported to lack introns and to belong to four different gene subfamilies. The subfamilies can display great sequence variability.
SUMMARY OF THE INVENTION
The invention is based in part on the discovery of a human nucleic acid sequence encoding a polypeptide showing homology to a bovine G-protein coupled receptor type B. This sequence was identified as a member of a set of nucleic acids that are differentially expressed in fibroblasts from individuals with conditions associated with tuberous sclerosis complex (TSC) relative to the expression of the nucleic acids in non-TSC fibroblasts. The set of differentially acids is referred to herein as “TSCX” nucleic acids, where “X” is an integer from 1 to 41. A TSC7 nucleic acid according to the invention can encode a G-protein coupled receptor.
The remaining differentially expressed nucleic acids include previously undescribed sequences and nucleic acids sequences that, while previously described, have not heretofore been identified as being expressed in altered levels in TSC individuals.
In one aspect, the invention provides isolated nucleic acid molecule encoding a polypeptide comprising an amino acid sequence of a polypeptide at least 85% identical to a TSCX polypeptide, e.g., a TSC7 polypeptide.
Also provided by the invention is a substantially purified TSCX polypeptide, as well as an antibody which specifically binds to a TSCX polypeptide.
In a further aspect, the invention provides a method of producing a TSCX polypeptide, by culturing a cell containing a TSCX nucleic acid molecule under conditions allowing for expression of a polypeptide encoded by the nucleic acid molecule.
In a still further aspect, the invention provides a method of detecting the presence of a TSCX nucleic acid molecule in a sample by contacting the sample with a nucleic acid probe or primer that selectively binds to the nucleic acid molecule, and then determining whether the nucleic acid probe or primer bound to the TSCX nucleic acid molecule is present in the sample.
In a further aspect, the invention provides a method of detecting the presence of a TSCX polypeptide in a sample by contacting the sample with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound. The complex is then detected, if present, thereby identifying the polypeptide in the sample.
In another aspect, the invention includes a method of modulating the activity of a TSCX polypeptide, e.g., a TSC7 polypeptide, by contacting a cell sample comprising the polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide.
In a still further aspect, the invention provides a method for screening for a modulator of activity or of latency or predisposition to a G protein-mediated disorder. The method includes contacting a test compound with a TSC7 polypeptide and determining if the test compound binds to the polypeptide. Binding of the test compound to the polypeptide indicates the test compound is a modulator of activity or of latency or predisposition to a disorder in G-protein mediated pathway method for screening for a modulator of activity or of latency or predisposition to a disorder in a G-protein mediated pathway, the method comprising:
In a further aspect, the invention includes administering a test compound to a test animal suffering from or at increased risk for the G-protein mediated pathway disorder. The test animal recombinantly expresses a polypeptide encoded by a TSC7 nucleic acid sequence. The method includes measuring expression the activity of the recombinantly expressed TSC7 polypeptide in the test animal, and measuring the activity of the polypeptide in a control animal that recombinantly expresses the polypeptide and is not at increased risk for the G-protein mediated pathway disorder. Expression of the polypeptide in the test animal and the control animal is compared. A change in the activity of the polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of activity or of latency or predisposition of a G-protein mediated pathway.
In a further aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of an TSCX polypeptide in a subject. The method includes measuring the amount of the polypeptide in a sample from the subject, and comparing the amount of the polypeptide to the amount of the polypeptide present in a control sample. An alteration in the level of the polypeptide in step (a) as compared to the level of the polypeptide in the control sample indicates the presence of or predisposition to a disease in the subject.
In another aspect, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a TSCX nucleic acid molecule. The method includes measuring the amount of the TSCX nucleic acid in a sample from the subject, and comparing the amount of the nucleic acid in step to the amount of the nucleic acid present in a control sample. An alteration in the level of the nucleic acid in the sample as compared to the level of the nucleic acid in the control sample indicates the presence of or predisposition to the disease in the subject.
In a further aspect, the invention provides a method of treating or preventing a pathological condition associated with a disorder in a G-protein mediated pathway by administering a TSC7 polypeptide to a subject in an amount sufficient to alleviate or prevent the disorder.
Also included in the invention is a method of treating or preventing a pathological condition associated with a disorder in a G-protein mediated pathway. The method includes administering a TSC7 nucleic acid to a subject in an amount sufficient to treat or prevent the condition.
In another aspect, the invention includes a method of treating or preventing a pathological condition by administering an antibody to a TSCX polypeptide to a subject in an amount sufficient to alleviate or prevent the pathological condition.
Also included in the invention is a pharmaceutical composition that includes an TSCX nucleic acid, a TSCX polypeptide, and/or an antibody to a TSCX polypeptide, and a pharmaceutically acceptable carrier.
Also provided by the invention is a method of diagnosing a hyperproliferative disorder in a subject. The method includes providing a test cell population from the subject, wherein at least one cell in the test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of TSCs: 1-41 and measuring the expression of one or more the nucleic acid sequences in the test cell population. The expression of the nucleic acid sequences is compared to the expression of the nucleic acid sequences in a reference cell population comprising at least one cell whose status with respect to a hyperproliferative disorder is known A difference in expression levels of the TSC sequence, if present, is identified in the test cell population and reference cell population, thereby diagnosing the hyperproliferative disorder in the subject. If desired, expression of one or more genes encoding amartin, tuberin, rap1a, rab5, rabaptin-5, and alpha B crystallin is also compared.
Also provided in the invention is a method of treating a hyperproliferative condition, e.g., a neoplasm and/or a dermatological c

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