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(Received for publication, December 3, 1996, and in revised form, May 5, 1997)
and
From the Division of Endocrinology, Department of Medicine, Brown
University School of Medicine, Rhode Island Hospital, Providence,
Rhode Island 02903 and the The post-translational processing of
prothyrotropin-releasing hormone (pro-TRH25-255) has
been extensively studied in our laboratory, and the processing pathway
to mature TRH has been elucidated. We have also demonstrated that
recombinant PC1 and PC2 process partially purified pro-TRH to cryptic
peptides in vitro and that pro-TRH and PC1 mRNAs are
coexpressed in primary cultures of hypothalamic neurons. To further
define the role of each convertase, and particularly PC1 and PC2, in
pro-TRH processing, recombinant vaccinia viruses were used to coexpress
the prohormone convertases PC1, PC2, PACE4, PC5-B, furin, or control
dynorphin together with rat prepro-TRH in constitutively secreting LoVo cells or in the regulated endocrine GH4C1 cell line.
Radioimmunoassays from LoVo-derived secreted products indicated that
furin cleaves the precursor to generate both N- and C-terminal intermediates. PC1, PC2, and PACE4 only produced N-terminal
intermediates, but less efficiently than furin. In GH4C1 cells, PC1,
PC2, furin, PC5-B, and PACE4 produced both N-terminal and C-terminal
forms. Significantly, TRH-Gly and TRH were mostly produced by PC1, PC2, and furin. Utilizing gel electrophoresis to further analyze the cleavage specificities of PC1 and PC2, we found that PC1 seems primarily responsible for cleavage to both intermediates and mature TRH, since it generated all products at significantly higher levels than PC2. The addition of 7B2 to the coinfection did not augment the
ability of PC2 to cleave pro-TRH to either N- or C-terminal forms.
Laboratory of Biochemical
Neuroendocrinology, Clinical Research Institute of Montreal,
Montreal, Quebec H2W1R7, Canada
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