Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice.
Prohormone convertases (PCs) are thought to represent the major proteinases involved in the biosynthetic processing of peptide hormone precursors to bioactive peptide products. The maturation of PC2 requires the aid of a helper protein, 7B2, in order for the zymogen to become an active enzyme species. The 7B2 and PC2 nulls should thus be functionally equivalent with regard to deficits in precursor processing. In this article, we have examined this proposition through the study of proopiomelanocortin (POMC) biosynthesis and granule content in both null models. RIA data indicate that both PC2 and 7B2 nulls lack pituitary alpha-MSH; interestingly, 7B2 nulls are still able to generate beta-endorphin from beta-lipotropin, whereas PC2 nulls contain little if any beta-endorphin. Labeling experiments demonstrate a build-up of POMC, high molecular weight intermediates, and intact ACTH, as well as the disappearance of alpha-MSH, in both null models. Electron microscopy of neurointermediate lobe melanotrophs reveals the presence of a significantly greater number of secretory granules in both 7B2 and PC2 nulls compared with wild-type controls. However, PC2 null melanotrophs contain twice as many granules as 7B2 null melanotrophs. Another difference between the two null models is a relatively enhanced accumulation of precursors in the PC2 null compared with the 7B2 null; these include not only PC2 substrates, but also presumed PC1 substrates. These data indicate that the two nulls are not phenotypically equivalent.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA.
Virginie
V
Laurent
Lisa
L
Jaubert-Miazza
Roxane
R
Desjardins
Robert
R
Day
Iris
I
Lindberg
D000324:Adrenocorticotropic Hormone / Q000032:analysis; D000818:Animals; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000502:physiology; D051859:Neuroendocrine Secretory Protein 7B2; D010902:Pituitary Gland / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D010907:Pituitary Hormones / Q000172:deficiency* / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D045706:Proprotein Convertase 2 / Q000172:deficiency* / Q000502:physiology; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D000521:alpha-MSH / Q000032:analysis; D001615:beta-Endorphin / Q000032:analysis / Q000096:biosynthesis; D008083:beta-Lipotropin / Q000378:metabolism
D009419:Nerve Tissue Proteins; D051859:Neuroendocrine Secretory Protein 7B2; D010907:Pituitary Hormones; D011498:Protein Precursors; D012333:RNA, Messenger; D000521:alpha-MSH; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D008083:beta-Lipotropin; D045706:Proprotein Convertase 2