Inhibition of nuclear hormone receptor activity by calreticulin.
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.
Dedhar
S
S
Division of Cancer Research, University of Toronto, Ontario, Canada.
Rennie
P S
PS
Shago
M
M
Hagesteijn
C Y
CY
Yang
H
H
Filmus
J
J
Hawley
R G
RG
Bruchovsky
N
N
Cheng
H
H
Matusik
R J
RJ
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
D059002:Androgen Receptor Antagonists; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D016023:Integrins; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; D012261:Ribonucleoproteins; D004247:DNA