title: Inhibition of nuclear hormone receptor activity by calreticulin.
abstract: We have shown that a polypeptide of M(r) 60,000 (60K) that shares N-terminal homology with a calcium-binding protein, calreticulin, can bind to an amino-acid sequence motif, KXGFFKR, found in the cytoplasmic domains of all integrin alpha-subunits. The homologous amino-acid sequence, KXFFKR (where X is either G, A or V), is also present in the DNA-binding domain of all known members of the steroid hormone receptor family; amino acids in this sequence make direct contact with nucleotides in their DNA-responsive elements and are crucial for DNA binding. Here we show that both the 60K protein (p60), purified on a KLGFFKR-Sepharose affinity matrix, and recombinant calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element in a KXFFKR-sequence-specific manner. Calreticulin can also inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Our results indicate that calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
authors.affiliation: Division of Cancer Research, University of Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Dedhar
authors.forename: P S
authors.initials: PS
authors.lastname: Rennie
authors.forename: M
authors.initials: M
authors.lastname: Shago
authors.forename: C Y
authors.initials: CY
authors.lastname: Hagesteijn
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Filmus
authors.forename: R G
authors.initials: RG
authors.lastname: Hawley
authors.forename: N
authors.initials: N
authors.lastname: Bruchovsky
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: R J
authors.initials: RJ
authors.lastname: Matusik
mesh_terms: D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D037282:Calreticulin; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D016023:Integrins / Q000378:metabolism; D008969:Molecular Sequence Data; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012261:Ribonucleoproteins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014709:Vero Cells
chemical_list: D059002:Androgen Receptor Antagonists; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D016023:Integrins; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; D012261:Ribonucleoproteins; D004247:DNA