Structure of the Gene for the Testis-Specific Proprotein Convertase 4 and of Its Alternate Messenger RNA Isoforms

Mbikay, Majambu; Raffin-Sanson, Marie-Laure; Tadros, Haidy; Sirois, Francine; Seidah, Nabil G.; Chrétien, Michel

doi:10.1006/geno.1994.1158

Cited by 39 publications

(25 citation statements)

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“…1) are the major forms expressed in the neuroendocrine system and brain, where they act on prohormone and neuropeptide precursors within dense core vesicles of the regulated secretory pathway (9,13). PC4, which is expressed only in the testis (55), and an isoform of PC6 that lacks a TM domain, PC6A, also belong to this group (34). The differential expression of PC2 and PC1/PC3 in various endocrine cells and neurons gives rise to varied mixtures of peptide products with divergent or opposing activities, sometimes derived from the same precursor (Fig.…”

Section: Two Major Functional Branchesmentioning

confidence: 99%

Proteolytic Processing in the Secretory Pathway

Zhou¹,

Webb²,

Zhu³

et al. 1999

Journal of Biological Chemistry

452

414

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Section: Two Major Functional Branchesmentioning

confidence: 99%

Proteolytic Processing in the Secretory Pathway

Zhou¹,

Webb²,

Zhu³

et al. 1999

Journal of Biological Chemistry

452

414

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“…Of these PCs, furin, PACE4, PC5͞PC6, and PC7 exhibit widespread tissue distribution, whereas PC1 and PC2 are expressed only in endocrine and neuroendocrine tissues and cells. Of the proprotein convertases, PC4 is interesting in being expressed solely in reproductive tissues, and the presence of PC4 outside of the gonads (testis and ovary) has never been documented (18)(19)(20).…”

mentioning

confidence: 99%

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development

Qiu

Basak

Mbikay

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Fetal growth restriction (intrauterine growth restriction, IUGR) is a leading cause of perinatal mortality. However, the causes of aberrant development of the placenta and, thus, of the fetus, are not currently known. Insulin-like growth factor II (IGF-II) has been shown to be an important regulator of fetoplacental growth. This growth factor must undergo posttranslational processing, and, thus, we hypothesized that aberrant processing of pro-IGF-II to IGF-II may be a cause of IUGR. Here, we have found that the proprotein convertase PC4 is expressed in the human placenta and that it cleaves pro-IGF-II to generate the intermediate processed form, IGF-II (1-102) and, subsequently, mature IGF-II (1-67), which are accounted for by the removal of terminal basic residues by carboxypeptidases. This processing confers the ability of IGF-II to activate invasive trophoblast cells through AKT phosphorylation, whereas inhibition of PC4 by a PC4-specific inhibitor blocks pro-IGF-II processing and reduces trophoblast cell migration, which can be partly restored by addition of mature IGF-II. Consistent with the hypothesis that IGF-II processing is implicated in IUGR, sera of patients carrying IUGR fetuses displayed elevated levels of pro-IGF-II. Thus, abnormal processing of IGF-II by PC4 may represent a previously uncharacterized mechanism involved in the pathophysiology of fetoplacental growth restriction, and elevated pro-IGF-II may be a useful clinical marker for risk of IUGR.insulin-like growth factor II ͉ intrauterine growth restriction

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“…Previous reports of the structural organization of the genes of mammalian prohormone convertases have demonstrated a high degree of conservation in the gene organization of this enzyme family [6,[29][30][31][32][33]. A comparison of intron-exon splice junctions of hPC8 with those of hPC1, hPC2, hPACE, mouse (m)PC4 and human furin genes illustrated a distinctive divergence of the gene organization of human PC8 from the striking conservation of splice boundaries observed in the gene organizations of other convertase family members.…”

Section: Structure Of the Hpc8 Genementioning

confidence: 80%

“…In agreement with this proposition was the ubiquitous nature of the mRNA tissue distribution for PC8 [19,21], although the varying mRNA expression in certain tissues suggests that some cells might have altered transcriptional activation of PC8, or might confer altered mRNA stability for PC8. The absence of classical TATA or CAAT promoter elements is characteristic of many promoter regions reported for other prohormone convertase genes, including PC2, PC4 and the P1A and P1B promoter region of furin [29,32,40].…”

Section: At the 5h End Of The Hpc8 Genementioning

confidence: 99%

Gene organization and alternative splicing of human prohormone convertase PC8

Goodge

Thomas

Martın

et al. 1998

Biochemical Journal

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The mammalian Ca2+-dependent serine protease prohormone convertase PC8 is expressed ubiquitously, being transcribed as 3.5, 4.3 and 6.0 kb mRNA isoforms in various tissues. To determine the origin of these various mRNA isoforms we report the characterization of the human PC8 gene, which has been previously localized to chromosome 11q23–24. Consisting of 16 exons, the human PC8 gene spans approx. 27 kb. A comparison of the position of intron–exon junctions of the human PC8 gene with the gene structures of previously reported prohormone convertase genes demonstrated a divergence of the human PC8 from the highly conserved nature of the gene organization of this enzyme family. The nucleotide sequence of the 5´-flanking region of the human PC8 is reported and possesses putative promoter elements characteristic of a GC-rich promoter. Further supporting the potential role of a GC-rich promoter element, multiple transcriptional initiation sites within a 200 bp region were demonstrated. We propose that the various mRNA isoforms of PC8 result from the inclusion of intronic sequences within transcripts.

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Structure of the Gene for the Testis-Specific Proprotein Convertase 4 and of Its Alternate Messenger RNA Isoforms

Cited by 39 publications

References 0 publications

Proteolytic Processing in the Secretory Pathway

Proteolytic Processing in the Secretory Pathway

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development

Gene organization and alternative splicing of human prohormone convertase PC8

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