Abstract
cDNA analyses predict that the human calcitonin gene encodes the two precursor proteins of calcitonin and calcitonin gene-related peptide (CGRP). The mRNAs for the putative precursors of these peptides are derived from alternative processing of the primary transcript of this gene. The 75 amino-terminal residues of each preprohormone are predicted to be identical. We have developed the TT human medullary thyroid carcinoma cell line as a model to study human calcitonin gene expression. Mature calcitonin and CGRP are major secretory products of this cell line. Extracts of TT cells radiolabeled with amino acids for 1 h contained only one peak of either immunoprecipitable calcitonin or CGRP on reverse-phase high-pressure liquid chromatography. Each of these species had an Mr = 12,800 as estimated by gel filtration chromatography. The results of partial amino-terminal microsequencing of these two precursors were identical. Residues 2, 11, and 14 of each precursor were proline, and residues 7, 17, 24, 25, 26, and 29 were leucine. The unique alignment of the positions of these amino acids with the cDNA-predicted sequence for the common region of preprocalcitonin and preproCGRP suggests that the site of signal sequence cleavage occurs after residue 25 of both preprophormones. These studies represent the first identification of procalcitonin (116 amino acids) from a human cell line and of proCGRP (103 amino acids) from any tissue.
Highlights
CDNA analyses predict that the human calcitonin toninand preproCGRP willbe identical, whereas the cargene encodes the two precursor proteinsof calcitonin boxyl-terminal regions contain sequences specific for each of and calcitoningene-relatedpeptide (CGRP)
Extracts tion of human calcitonin mRNA [11]. there is of TT cells radiolabeled with amino acids fo1r h con- considerable sequence homology between the amino terminus tained only one peoakf either immunoprecipitable cal- of rat preprocalcitonin and the cDNA-predicted sequence of cTc1hi2htro,eo8nm0irn0aetosaoursglCertsaosGptfiRhpmyPaa.rttEeioaadnlchbaryemvoigfenertoslhe-etf-esiplerhtmrsaapistneeiaoclinheismgchhhiacr-dopromresaaesnstqouuMgreern,acp=liihnqygu.ctsihdtlereuaccvotaumgreemsoofonfthrheeugmihoaunnmofpatrnhoecsaihglcunimatolannsienpqrauenecnducrpsero,oraCsn,GdthRetPhee,xrceaafcnot rnseoittethboeef of these two precursors were identicRale. sidues 2, 1 1, predicted with certainty. and 14 of each precursor were proline, and residu7e,s Both calcitonin and CGRP have been identified in normal
Thyroid carcinoma [15, 16]. mRNA encoding precursor proteins of calcitonin andCGRPand large molecular weight putative precursor forms of calcitonin have been identified in lung-cancer cell lines that do not produce M, = 3400 calcitonin [17,18,19,20,21,22]
Summary
CDNA analyses predict that the human calcitonin toninand preproCGRP willbe identical, whereas the cargene encodes the two precursor proteinsof calcitonin boxyl-terminal regions contain sequences specific for each of and calcitoningene-relatedpeptide (CGRP). The unique align- thyroid tissue [12,13,14] and in extracts of human medullary ment of the positions of these amino acids with the cDNA-predicted sequence for the common region of preprocalcitonin and preproCGRP suggests that the site of signal sequence cleavage occurs after residue 25 of both preprophormones.
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