Previously, Guillemin and Rosenberg1 and Saffran and Schally2 demonstrated the presence of hypothalamic factors that stimulated the secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland. Recently, Vale et al.3,4 have isolated and sequenced an ovine hypothalamic peptide of 41 amino acids, which is believed to represent the major physiological corticotropin-releasing factor (CRF) (reviewed in refs 5, 6). Available data suggest that hypothalamic CRF enhances both the synthesis and secretion of ACTH and related peptides such as β-endorphin and β-lipotropin (β-LPH) (reviewed in ref. 6), which are all derived from the common precursor, termed ACTH-β-LPH precursor or preproopiomelanocortin (reviewed in ref. 7). Because CRF mediates the neural control of the pituitary-adrenocortical system, the characterization of its biosynthetic precursor and the gene encoding it is essential for understanding the molecular mechanism underlying the endocrine response to stress. We have now cloned DNA sequences complementary to the ovine hypothalamic mRNA encoding the CRF precursor (referred to hereafter as prepro-CRF). The nucleotide sequence of the cloned cDNA, reported here, has revealed the primary structure of prepro-CRF. The carboxyl end represents the CRF sequence preceded by the tetrapeptide, Arg-Lys-Arg-Arg, and followed by the dipeptide, Gly-Lys. Comparison of the amino acid sequence of prepro-CRF with those of the ACTH-β-LPH precursor and the arginine vasopressin-neurophysin II precursor8 suggests that these precursor proteins may be evolutionarily related.
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