Sphingosine-1-phosphate lyase polypeptides, polynucleotides and modulating agents and methods of use therefor
AssigneeChildren's Hospital & Research Center at Oakland
InventorsJulie D. Saba, Jianhui Zhou
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Abstract
Compositions, methods and kits for diagnosing and treating cancer are provided. Therapeutic compositions may comprise agents that modulate the expression or activity of a sphingosine-1-phosphate lyase (SPL). Such compositions may be administered to a marnmal afflicted with cancer. Diagnostic methods and kits may employ an agent suitable for detecting alterations in endogenous SPL. Such methods and kits may be used to detect the presence of a cancer or to evaluate the prognosis of a known disease. SPL polypeptides, polynucleotides and antibodies are also provided.
Claims51
An isolated polynucleotide comprising a sequence selected from the group consisting of:
- (a) a sequence recited in SEQ ID NO:
- 1;
- (b) a sequence recited in SEQ ID NO:
- 3;
- (c) nucleotide sequences that hybridize to a polynucleotide complementary to either of the foregoing sequences under moderately stringent conditions, wherein the nucleotide sequences encode polypeptides having sphingosine-1-phosphate lyase activity;
- and
- (d) nucleotide sequences that encode a polypeptide encoded by any of the foregoing sequences.
An isolated polynucleotide encoding a polypeptide recited in SEQ ID NO:
- 2, or a variant of such a polypeptide that has sphingosine-1-phosphate lyase activity.
An isolated polynucleotide encoding a polypeptide comprising a sequence recited in SEQ ID NO:
- 4, or a variant of such a polypeptide that has sphingosine-1-phosphate lyase activity.
An isolated polynucleotide comprising at least 100 nucleotides complementary to a sequence recited in SEQ ID NO:
- 1 or 3.
A polypeptide comprising an amino acid sequence recited in SEQ ID NO:
- 2 or 4, or a variant thereof, wherein the polypeptide has sphingosine-1-phosphate lyase activity.
A method for identifying an agent that modulates sphingosine-1-phosphate lyase activity, comprising:
- (a) contacting a candidate agent with cells that express sphingosine-1-phosphate lyase;
- and
- (b) subsequently measuring the level of sphingosine-1-phosphate lyase or mRNA encoding sphingosine-1-phosphate lyase in the cells, relative to a predetermined level in the absence of candidate agent, and therefrom identifying an agent that modulates sphingosine-1-phosphate lyase activity.
A method for identifying an agent that modulates sphingosine-1-phosphate lyase activity, comprising:
- (a) contacting a candidate agent with a polypeptide comprising a sequence recited in any one of SEQ ID NOs:
- 2, 4, 6 or 8, or a variant of such a sequence having sphingosine-1-phosphate lyase activity, wherein the step of contacting is carried out under conditions and for a time sufficient to allow the candidate modulator to interact with the polypeptide;
- and
- (b) subsequently measuring the ability of the polypeptide to degrade sphingosine-1-phosphate or a derivative thereof, relative to an ability in the absence of candidate agent, and therefrom identifying an agent that modulates sphingosine-1-phosphate lyase activity.
A pharmaceutical composition comprising an agent that modulates sphingosine-1-phosphate lyase activity in combination with a pharmaceutically acceptable carrier.
A method for modulating sphingosine-1-phosphate lyase activity, comprising contacting a sphingosine-1-phosphate lyase with an effective amount of an agent that modulates sphingosine-1-phosphate lyase activity, wherein the step of contacting is performed under conditions and for a time sufficient to allow the agent and the sphingosine-1-phosphate lyase to interact.
A method for inhibiting the growth of a cancer cell, comprising contacting a cancer cell with an agent that inhibits sphingosine-1-phosphate lyase activity.
A method for inhibiting the development and/or metastasis of a cancer in a mammal, comprising administering to a mammal an agent that inhibits sphingosine-1-phosphate lyase activity.
A method for diagnosing a cancer in a mammal, comprising detecting an alteration in an endogenous sphingosine-1-phosphate lyase gene in a sample obtained from a mammal, and therefrom diagnosing a cancer in the mammal.
A method for evaluating a cancer prognosis, comprising determining the presence or absence of an alteration in an endogenous sphingosine-1-phosphate lyase gene in a sample obtained from a mammal afflicted with cancer, and therefrom determining a prognosis.
An isolated antibody that binds to a polypeptide having a sequence recited in any one of SEQ ID NOs:
- 2, 4 or 6.
A monoclonal a ntibody that binds to a polypeptide having a sequence recited in any one of SEQ ID NOs:
- 2, 4 or 6.
A transgenic animal in which sphingosine-1-phosphate lyase activity is reduced compared to a wild-type animal.
Dependencies are inferred from the claim text.