Novel use of calreticulin in modulating hormone responsiveness and new pharmaceuticals for treating cancer, osteoporosis and chronic inflammatory disease

Abstract

This invention relates to isolated and purified proteins, such as calreticulin and mimetics of calreticulin, for a novel use of modulating hormone responsiveness. These proteins are useful in gene therapy and in manufacturing pharmaceuticals for treating a variety of diseases, including cancer, osteoporosis and chronic inflammatory disease. The proteins include or bind to an amino acid sequence KXFFYR, wherein X is either G, A or V and Y is either K or R. This sequence is present in the DNA-binding domain, and is critical for the DNA binding activity, of a variety of hormone receptors, including glucocorticoid receptor, minerolcorticoid receptor, androgen receptor, progesterone receptor, estrogen receptor, retinoic acid receptor, thyroid hormone receptor and vitamin D receptor. Proteins which bind to this sequence may inhibit hormone receptor induced gene transcription. Proteins which include this sequence may promote hormone receptor induced gene transcription. The invention includes isolated DNA molecules for these proteins, methods of treating diseases using these proteins, synthetic peptides and their mimetics, and kits containing these proteins, synthetic peptides or their mimetics.

We claim:  
     
         1 . An isolated and purified product for use in modulating hormone responsiveness.  
     
     
         2 . The product of  claim 1 , wherein the product inhibits hormone receptor induced gene transcription.  
     
     
         3 . The product of  claim 1 , wherein the product promotes hormone receptor induced gene transcription.  
     
     
         4 . The product of  claim 2 , wherein the product binds to the amino acid sequence KXFFYR, wherein X is G, A or V and wherein Y is K or R and wherein the product is selected from a group consisting of calreticulin and a mimetic of calreticulin.  
     
     
         5 . The product of claim  claim 3 , wherein the product comprises the amino acid sequence KXFFYR, wherein X is G, A or V and wherein Y is K or R, and wherein the product is a synthetic peptide which binds to calreticulin.  
     
     
         6 . An isolated DNA molecule encoding an amino acid sequence for use in modulating hormone responsiveness.  
     
     
         7 . The isolated DNA molecule of  claim 6 , wherein the molecule encodes a first amino acid sequence that binds to a second amino acid sequence KXFFYR, wherein X is G, A or V and wherein Y is K or R, and wherein the first amino acid sequence is the sequence for calreticulin or for part of a mimetic of calreticulin.  
     
     
         8 . A method of treating a disease in a mammal comprising regulating hormone receptor induced gene transcription in a cell.  
     
     
         9 . The method of  claim 8 , further comprising regulating the activity, quantity or stability of a protein for use in hormone receptor induced gene transcription.  
     
     
         10 . The method of  claim 9 , further comprising administering to the mammal a pharmaceutical comprising the protein and a carrier.  
     
     
         11 . The method of  claim 9 , wherein the protein binds to the amino acid sequence KXFFYR, wherein X is G, A or V and wherein Y is K or R.  
     
     
         12 . The method of  claim 9 , wherein the protein is one selected from a group consisting of calreticulin and a mimetic of calreticulin, and wherein the carrier is a lipid vesicle.  
     
     
         13 . The method of  claim 8 , wherein the disease is one selected from a group consisting of breast cancer, prostate cancer, promyelocytic leukemia, solid tumors, chronic inflammatory disease, arthritis, and osteoporosis.  
     
     
         14 . The method of  claim 8 , further comprising decreasing or eliminating the quantity of calreticulin present in the cell.  
     
     
         15 . The method of  claim 8 , further comprising decreasing the stability of calreticulin present in a cell.  
     
     
         16 . The method of  claim 8 , wherein the hormone receptor is one selected from a group consisting of: glucocorticoid receptor, minerolcorticoid receptor, androgen receptor, progesterone receptor, estrogen receptor, retinoic acid receptor, thyroid hormone receptor, vitamin D receptor and orphan receptors.  
     
     
         17 . A kit containing a pharmaceutical comprising a protein for use in modulating hormone responsiveness together with a carrier.  
     
     
         18 . The kit of  claim 17 , wherein the protein binds to the amino acid sequence KXFFYR, wherein X is G, A or V and wherein Y is K or R and wherein the protein is calreticulin or a mimetic of calreticulin.  
     
     
         19 . The kit of  claim 17 , wherein the carrier is a lipid vesicle.