Disease relevance of Pcsk1

• A 5.0-kilobase (kb) cDNA, termed BDP, coding for a 752-amino acid protein and a 2.5-kb cDNA coding for a 636-amino acid protein, which was found to be the rat equivalent of the human insulinoma PC2 protein, were isolated [1].
• In the adenopituitary, POMC mRNA levels were decreased after dehydration but PC1 mRNA levels were unaffected [2].
• Infection of INS cells with the corresponding recombinant adenovirus led to 5-10-fold and 20-40-fold increases in PC2 and PC3 expression respectively [3].
• To investigate whether prohormone convertases are involved in ProNPY processing, a vaccinia virus derived expression system was used to coexpress recombinant ProNPY with each of the prohormone convertases PC1/3, PC2, furin, and PACE4 in Neuro2A and NIH 3T3 cell lines as regulated neuroendocrine and constitutive prototype cell lines, respectively [4].
• In this study, we demonstrated that 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism stimulated, whereas triido-L-thyronine (T(3))-induced hyperthyroidism suppressed, PC1 mRNA levels in the rat anterior pituitary [5].

Psychiatry related information on Pcsk1

• The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease [6].

High impact information on Pcsk1

• A decrease in the islet content of PC2, PC3, and CP-H from hyperglycemic rats was observed [7].
• The assay reconstitutes homotypic fusion between one population of ISGs containing a [35S]sulfate-labeled substrate, secretogranin II (SgII), and a second population containing the prohormone convertase PC2 [8].
• In the present work we have stably transfected neuroendocrine cell lines with rat 7B2 constructs and found that overexpression of 27 kD 7B2 greatly facilitates the kinetics of maturation of proPC2, both in AtT-20/PC2 cells and in Rin5f cells [9].
• To correlate effects on PC2 maturation with the actual generation of PC2 enzymatic activity, a similar transfection of 21 kD 7B2 was performed using CHO cells previously amplified for the expression of proPC2 [9].
• The prohormone convertase PC2, which is thought to mediate the proteolytic conversion of many peptide hormones, has recently been shown to interact with the neuroendocrine-specific polypeptide 7B2 in Xenopus intermediate lobe (Braks, J. A. M., and G. J. M. Martens. Cell. 78:263. 1994) [9].

Chemical compound and disease context of Pcsk1

• Proprotein convertase PC4A, a member of the subtilisin/kexin family of serine proteases, was obtained in enzymically active form following expression of vaccinia virus recombinant rat (r)PC4A in GH4C1 cells [10].
• Androgen-mediated growth repression of androgen-independent prostate cancer (AIPC) cells has been reported in androgen-independent PC-3 cells overexpressing the androgen receptor, and in androgen-independent derivatives of LNCaP cells that develop following prolonged culture in androgen-free media [11].
• The difference in gene expression between the highly invasive and metastatic cell line PC-1.0 and the weakly invasive and metastatic cell line PC-1 both derived from a pancreatic ductal carcinoma induced by N-nitrosobis (2-oxopropyl) amine (BOP) in Syrian golden hamster was examined using the Representational Difference Analysis (RDA) method [12].

Biological context of Pcsk1

• Further transfection analysis identified the sorting sequence as a compact C-terminal alpha-helix and embedded 564RRR566 PC cleavage site; mutation of the 564RRR566 PC site in VGF-(1-65): GFP:VGF-(545-617) blocked regulated secretion, whereas disruption of the alpha-helix had no effect [13].
• During the development of rat pancreatic islets, the prohormone convertases, PC2 and PC3, appear during late gestation and are expressed long after birth [14].
• Among the convertases studied, only PC1 messenger RNA displayed up-regulation, with temporal and topographic features comparable to those of nerve growth factor and brain-derived neurotrophic factor messenger RNA [15].
• We conclude that PC2 is the key endoprotease responsible for proglucagon processing in cells with the alpha-cell phenotype [16].
• We speculate that (a) PC2 undergoes unusual glycosylation, which may be related to its slow release from cells, and (b) the 64-kDa molecule detectable in spent Rin cell medium represents the enzymatically active form of PC2 [17].

Anatomical context of Pcsk1

• We now report that when pro-TRH is transiently expressed in GH4C1 cells, a neuroendocrine cell line lacking PC1, under pulse-chase conditions release is constitutive and composed of more immature processing intermediates [18].
• These results indicated that initial processing action of PC1 on pro-TRH in the trans-Golgi network, and not a cargo-receptor relationship, is important for the downstream sorting events that result in storage of pro-TRH-derived peptides in mature secretory granules [18].
• Furthermore, pro-NT/NN was processed in these compartments according to a pattern that differed from that previously described in PC1- and PC2-transfected PC12 cells [19].
• This is in contrast to the processing of proinsulin to insulin in the pancreatic beta-cell, which is up-regulated by glucose stimulation of PC1 and PC2 synthesis [20].
• PC2 was found in A and in some D cells more than in B cells and PC1 was evident only in B cells [21].

Associations of Pcsk1 with chemical compounds

• A candidate endoprotease is prohormone convertase 1 (PC1) also known as PC3, a Ca2+-dependent serine endoprotease of the subtilisin family [22].
• Finally, inhibition of PC cleavage in PC12 cells using the membrane-permeable synthetic peptide chloromethyl ketone (decanoyl-RVKR-CMK) blocked regulated secretion of VGF [13].
• Thus, in the rat hippocampus, the epileptiform activity induced by pilocarpine mediates a co-ordinated expression of messenger RNAs for PC1, nerve growth factor and brain-derived neurotrophic factor [15].
• Expression of the proprotein convertases PC1 and PC2 mRNAs in thyrotropin releasing hormone neurons of the rat paraventricular nucleus of hypothalamus [23].
• PC1 also generated a peptide which after carboxypeptidase B treatment, was detected with an antiserum specific for CCK Gly [24].

Co-localisations of Pcsk1

• The proprotein convertase furin colocalizes with caveolin-1 in the Golgi apparatus and endosomes of hepatocytes [25].

Regulatory relationships of Pcsk1

• A moderate to high percentage of CCK mRNA-positive neurons express PC1 mRNA [26].
• METHODS AND RESULTS: Here, we show that after MI, the expression of pro-TRH is induced in the heart coordinately with the protease PC1, an important enzyme in TRH biosynthesis [27].
• In general, PC2 was more widely expressed than PC1 in the CNS, although many regional variations were detected [28].

Other interactions of Pcsk1

• Prohormone convertase 1 is necessary for the formation of cholecystokinin 8 in Rin5F and STC-1 cells [22].
• We quantified, by two different approaches, in situ hybridization (ISH) on consecutive cryostat sections or double label ISH, the proportion of PVN TRH neurons containing either PC1 or PC2 mRNAs [23].
• Stepwise posttranslational processing of progrowth hormone-releasing hormone (proGHRH) polypeptide by furin and PC1 [29].
• Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1) [30].
• The long-form membrane leptin receptor OB-Rb, the protease activator furin, and proprotein convertase 7 were found in Chief cell granules but not in those of endocrine cells [31].

Analytical, diagnostic and therapeutic context of Pcsk1

• Constitutive expression of antisense PC1 message in stably transfected Rin5F cells resulted in a significant reduction of the cellular content of CCK 8 as measured by radioimmunoassay [22].
• Pro CCK was expressed in an L cell line engineered to express PC1 and the products secreted into the media were characterized by a combination of RIA, gel filtration and HPLC [24].
• The presence of the convertases PC1 and PC2 was determined by Western blot analysis of cellular extracts and fluorescence immunocytochemistry [32].
• The mRNAs for two other related endopeptidases, prohormone convertase 1 and 2, were not detected on Northern blots, suggesting that these enzymes are not required for the processing of prodynorphin [33].
• One of the clones, R1E8, expresses antisense PC1 mRNA as determined by reverse transcriptase-PCR (RT-PCR) and contains a significantly reduced level of PC1 protein [34].

References