Identification of a new class of steroid hormone receptors

The gonads and adrenal glands produce steroids classified into five major groups which include the oestrogens, progestins, androgens, glucocorticoids and mineralocorticoids. Gonadal steroids control the differentiation and growth of the reproductive system, induce and maintain sexual characteristics and modulate reproductive behaviour. Adrenal steroids also influence differentiation as well as being metabolic regulators. The effects of each steroid depend primarily on its specific receptors, the nature of which could therefore provide a basis for classification of steroid hormone action. The successful cloning, sequencing and expression of the human glucocorticoid (hGR) (ref. 1), oestrogen2,3 (hER), progesterone4 (hPR), and mineralocorticoid5 (hMR) receptors, complementary DNA, plus homologues from various species6–11, provides the first opportunity to study receptor structure and its influence on gene expression. Sequence comparison and mutational analysis12,13 show structural features common to all groups of steroid hormone receptors. The receptors share a highly conserved cysteine-rich region which functions as the DNA-binding domain14,15. This common segment allows the genome to be scanned for related gene products: hMR cDNA for example, was isolated using an hGR hybridization probe5. In this study, using the DNA-binding domain of the human oestrogen receptor cDNA as a hybridization probe, we have isolated two cDNA clones encoding polypeptides with structural features suggestive of cryptic steroid hormone receptors which could participate in a new hormone response system.

[1]  P Berg,et al.  Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. , 1977, Journal of molecular biology.

[2]  G. I. Bell,et al.  Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. , 1986, Nucleic acids research.

[3]  M. Kozak,et al.  Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo , 1984, Nature.

[4]  I. Weiler,et al.  The Xenopus laevis estrogen receptor: sequence homology with human and avian receptors and identification of multiple estrogen receptor messenger ribonucleic acids. , 1987, Molecular endocrinology.

[5]  J. Northrop,et al.  The mouse glucocorticoid receptor: mapping of functional domains by cloning, sequencing and expression of wild‐type and mutant receptor proteins. , 1986, The EMBO journal.

[6]  R. Evans,et al.  Colocalization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptor , 1987, Cell.

[7]  M. Haussler,et al.  Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. , 1987, Science.

[8]  B. O’Malley,et al.  Structural organization and regulation of the chicken estrogen receptor. , 1987, Molecular endocrinology.

[9]  J. Shine,et al.  Sequence and expression of human estrogen receptor complementary DNA. , 1986, Science.

[10]  R. Evans,et al.  Primary structure and expression of a functional human glucocorticoid receptor cDNA , 1985, Nature.

[11]  J. Devereux,et al.  A comprehensive set of sequence analysis programs for the VAX , 1984, Nucleic Acids Res..

[12]  P Argos,et al.  The chicken oestrogen receptor sequence: homology with v‐erbA and the human oestrogen and glucocorticoid receptors. , 1986, The EMBO journal.

[13]  R. Evans,et al.  Functional domains of the human glucocorticoid receptor , 1986, Cell.

[14]  P. Argos,et al.  Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A , 1986, Nature.

[15]  D. Housman,et al.  Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. , 1987, Science.

[16]  K. Yamamoto,et al.  Genetic complementation of a glucocorticoid receptor deficiency by expression of cloned receptor cDNA , 1986, Cell.

[17]  W. Gilbert,et al.  A new method for sequencing DNA. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[18]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[19]  K. Yamamoto,et al.  Glucocorticoid receptor mutants that define a small region sufficient for enhancer activation. , 1987, Science.

[20]  R Staden,et al.  An interactive graphics program for comparing and aligning nucleic acid and amino acid sequences. , 1982, Nucleic acids research.

[21]  E. Milgrom,et al.  Cloning and sequence analysis of rabbit progesterone-receptor complementary DNA. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[22]  P. Chambon,et al.  Localisation of the oestradiol‐binding and putative DNA‐binding domains of the human oestrogen receptor. , 1986, The EMBO journal.

[23]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[24]  F. Galibert,et al.  Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA. , 1987, Biochemical and biophysical research communications.