| 摘要 |
Disclosed herein is an isolated polypeptide which binds to the DNA binding domain located from -550 to -487 in the promoter of the human TNF-alpha gene. This isolated polypeptide is referred to herein as the LITAF protein. Polypeptides of human origin are specifically provided. Also disclosed is a nucleic acid sequence which encodes the LITAF protein. Such nucleic acids may be incorporated into an expression vector, which may be inserted into a cell. LITAF dependent induction of TNF-alpha gene expression in a cell can be inhibited by delivering an inhibitor of expression of the LITAF gene to the cell. Such an inhibitor is for example an antisense construct which encodes an antisense RNA molecule which is complementary to a portion of the LITAF mRNA which is greater than 200 nucleotides in length. Preferably, the antisense RNA molecule is complementary to the start site of translation, upstream adjacent 5' untranslated sequence, and downstream adjacent coding sequence of the LITAF mRNA. Optimal lengths and specific nucleotides for complementary are discussed. Inhibition of LITAF dependent induction of TNF-alpha gene expression in a cell can also be achieved by contacting an inhibitor of LITAF protein function to the LITAF protein within a cell. Such an inhibitor may be an antibody which binds the LITAF protein, or alternatively a small molecule which inhibits the function of the LITAF protein. One example of such an inhibitor is a recombinant mutant LITAF protein. Administration of a LITAF inhibitor can be performed as a therapeutic method for treating a patient with a disease associated with chronic inflammation. Such diseases include rheumatoid arthritis, gum disease Crohn's disease, and graft-versus-host disease. Therapeutic methods for treating a patient with a disease in which TNF-alpha plays a role in pathology are also provided. Examples of such diseases are diabetes mellitus, cancer, cachexia, breast cancer, HIV, sepsis, malaria, trypanomiasis and asthma. Other methods provided include a method for identifying genes which are regulated by the LITAF protein, a method for identifying a molecule which inhibits LITAF binding to the TNF-alpha promoter, and a method for identifying molecules which bind LITAF from a protein array.
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