Disease relevance of Cpd

• A full-length, PRL-inducible complementary DNA (cDNA) encoding a novel, nuclear-targeted carboxypeptidase D isoform (designated CPD-N) was identified in the rat PRL-dependent Nb2-11C and PRL-independent Nb2-Sp lymphoma cell lines by differential display [1].
• Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo [2].
• Morphine (5 and 10 mg/kg), nalorphine (5 and 10 mg/kg) and naloxone (0.5 mg/kg) induced a significant rise of Cpd B 30 min after subcutaneous injection, however, this could be prevented by 300 mg/kg piracetam given intraperitoneally 60 min prior to decapitation [3].
• The partial N-terminal amino acid sequence of bovine CPD shows 30-40% homology with an N-terminal region of bovine and rat CPE and 70% homology with a duck protein known as gp180, a hepatitis B virus particle binding protein that shows 47% homology to CPE [4].

High impact information on Cpd

• Tissue distribution and characterization of soluble and membrane-bound forms of metallocarboxypeptidase D [5].
• The partial N-terminal amino acid sequences of the two soluble forms are identical to each other and to the predicted N terminus of duck gp180 [5].
• Using primary cultures of adult rat hepatocytes that are in G0/G1 phase until stimulated into DNA synthesis by epidermal growth factor, we found that 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone or Compound 5 (Cpd 5) inhibited hepatocyte DNA synthesis and PTP activity in cell culture and in vivo after a two-thirds partial hepatectomy [6].
• In contrast, HGF antagonized the growth inhibitory actions of Cpd 5 on normal rat hepatocytes, thus showing a selective effect on tumor cells compared to normal cells [7].
• We have previously shown that Compound 5 (Cpd 5), an inhibitor of protein phosphatase Cdc25A, inhibits Hep3B human hepatoma cell growth [7].

Chemical compound and disease context of Cpd

• DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration [2].

Biological context of Cpd

• The mouse Cpd gene maps to the medial portion of chromosome 11, approximately 45.5 cM distal to the centromere [8].
• Whereas active site, substrate-binding, and metal-binding residues of other metallocarboxypeptidases are conserved in the first two domains of CPD, several of the critical residues are not conserved in the third domain; this third domain is not predicted to form an active carboxypeptidase [8].
• EGFR tyrosine phosphorylation was induced by Cpd 5 in a time- and dose-dependent manner [9].
• The aim of this study was to determine if the inhibitory effect of Cpd 5 on cell growth was related to apoptosis [10].
• We have here examined the tissue distribution, in vivo tolerance and growth inhibitory effects of a single injected dose of Cpd 5 in rats [11].

Anatomical context of Cpd

• CPD mRNA is detectable in most tissues examined, and is most abundant in hippocampus, spinal cord, atrium of the heart, colon, testis, and ovaries [8].
• Plasma Cpd B responses to stimulation of the intermediate area of the lateral septal nucleus produced varying and inconsistent responses [12].
• Whereas no change in Cpd B levels were observed following sham stimulation or stimulation of the corpus callosum, fornix or anterior commissure, stimulation of the medial septal nuclei produced differential responses [12].
• We conclude that daily swimming for 9-10 days alters the numbers of cytoplasmic Cpd B binding sites in the face of increased adrenocortical activity, while not affecting dexamethasone binding in the cytosol fraction of myocardial tissue [13].
• Phosphopeptide maps and phosphoamino acid analysis of gpiv isolated from synaptic membranes and a postsynaptic glycoprotein of apparent Mr of 180,000 (gp180) isolated from synaptic junctions indicated that the former protein was identical to the previously identified postsynaptic-specific gp180 [14].

Associations of Cpd with chemical compounds

• A single dose of Cpd 5 also inhibited the formation of glutathione S-transferase-pi enzyme-altered cells induced by the hepatocarcinogen N-nitrosodiethylamine [15].
• Preincubation of the LDL samples with low micromolar concentrations (1 and 3 microM) of each agents for 30 min before the addition of copper resulted in significant delays of the lag time of LDL oxidation, and the effectiveness of Cpd B and Cpd C was more prominent than that mediated by either Trolox or probucol [16].
• The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1'-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed [16].
• A significant decrease in the binding capacity for corticosterone (Cpd B) was found 24 hours after the last swimming test, while the affinity constant remained unchanged [13].
• Piracetam in doses of 100, 300 and 600 mg/kg resulted in a progressive suppression of serum corticosterone concentration (Cpd B) as compared to the controls [3].

Enzymatic interactions of Cpd

• As in JM-1 cells in vitro, ERK1/2 was phosphorylated when rats in vivo were treated with Cpd 5 and tumor growth inhibition in vivo also was antagonized by treating rats with the ERK1/2 phosphorylation inhibitor PD098059 [15].

Regulatory relationships of Cpd

• CONCLUSIONS: The data suggest that the ERK signaling pathway may be involved in the regulation of rat hepatocyte apoptosis induced by Cpd 5 [10].
• Cpd 5 induced a cellular response program that included the induction of EGFR tyrosine phosphorylation and the activation of the mitogen-activated protein kinase (MAPK) cascade [9].
• Examination of upstream events of apoptosis pathway showed that the expression of Bax was induced and bcl-2 was inhibited by Cpd 5 treatment [10].

Other interactions of Cpd

• Identification and nuclear localization of a novel prolactin and cytokine-responsive carboxypeptidase D [1].
• EGF activated EGFR transiently, whereas Cpd 5 induced an intense and sustained activation [9].
• Coimmunoprecipitation studies demonstrated that both EGF and Cpd 5 induced tyrosine phosphorylation of EGFR was associated with increased amounts of adapter proteins Shc and Grb2, and the Ras GTP-GDP exchange protein Sos, indicating the formation of functional EGFR complexes [9].
• These results show that induction of ERK2 phosphorylation is likely involved in the mechanism by which Cpd 5 inhibits PH-induced DNA synthesis, probably as a result of its ability to inhibit the activity of ERK phosphatase(s) [11].
• This is supported by experiments with PD 153035 and PD 098059, antagonists of phosphorylation of EGFR and MAP kinase kinase (MEK), respectively, which both antagonized Cpd 5-induced phosphorylation and the inhibition of DNA synthesis [9].

Analytical, diagnostic and therapeutic context of Cpd

• Cloning and sequence analysis of cDNA encoding rat carboxypeptidase D [8].
• Northern blot analysis of CPD mRNA shows major bands of approximately 8 and 4 kb in many rat tissues, and additional species ranging from 1.4 to 5 kb that are expressed in some tissues or cell lines [8].
• In situ hybridization of CPD mRNA shows a distribution in many cells in rat brain and other tissues, with high levels in hippocampus, olfactory bulb, and the intermediate pituitary [8].
• Cpd 5 administered i.p. was sufficient to cause a 90% inhibition of the peak in DNA synthesis in rat liver 24 h after two-thirds partial hepatectomy (PH) [11].
• METHODS: Isolated rat hepatocytes were cultured with Cpd 5, and mitogen-activated signaling pathway and apoptosis pathway were investigated using Western blot analysis [10].

References