Disease relevance of Rgn

• SMP30-deficient (SMP30Y/-) mice are viable and fertile but lower in body weight and shorter in life span than the wild-type [1].

High impact information on Rgn

• We originally identified senescence marker protein 30 (SMP30) as a distinctive protein whose expression decreases in an androgen-independent manner with aging [2].
• Senescence marker protein 30 functions as gluconolactonase in L-ascorbic acid biosynthesis, and its knockout mice are prone to scurvy [2].
• The lactonase reaction with l-gulono-gamma-lactone is the penultimate step in l-ascorbic acid (AA) biosynthesis, and the essential role of SMP30 in this synthetic process was verified here by a nutritional study using SMP30 knockout mice [2].
• SMP30 purified from the rat liver had lactonase activity toward various aldonolactones, such as d- and l-glucono-delta-lactone, d- and l-gulono-gamma-lactone, and d- and l-galactono-gamma-lactone, with a requirement for Zn(2+) or Mn(2+) as a cofactor [2].
• SMP30-/- hepatocytes were found to be more susceptible to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) plus actinomycin D (ActD) than SMP30+/+ hepatocytes [3].

Chemical compound and disease context of Rgn

• A single intraperitoneal administration of calcium chloride (5, 15, and 30 mg Ca2+/100 g body weight) to mice induced a remarkable increase in regucalcin mRNA in the liver; the increase in regucalcin mRNA levels at 30 min after calcium administration was dose-dependent [4].

Biological context of Rgn

• Collectively, these results demonstrate that SMP30 acts to protect cells from apoptosis [3].
• We then investigated the tissue susceptibility for apoptosis induced by cytokine using primary cultured hepatocytes, because SMP30 could rescue cells from cell death caused by calcium influx, using a calcium ionophore as previously described [3].
• We have now characterized a unique property of SMP30, the hydrolysis of diisopropyl phosphorofluoridate (DFP), which is similar to the chemical warfare nerve agents sarine, soman and tabun [5].
• Conceivably, this abnormality of lipid metabolism is sufficient to curtail the life span of SMP30-deficient mice [1].
• The amino acid sequence of mouse regucalcin had 94% homology, as compared with that of rat regucalcin [4].

Anatomical context of Rgn

• To elucidate the physiological role of this protein, we introduced a null mutation of the SMP30 gene into the germ line of mice [3].
• Immunoreactivity against anti-SMP30 antibody was mainly detected in bronchial epithelial cells and strongly detected at 6-12 months of age [6].
• By reverse transcription-polymerase chain reaction analysis, SMP30 mRNA transcripts were found in the mouse lung, liver, kidney, testis and cerebrum [6].
• These results suggest that SMP30 may be closely related to a signal transduction pathway in the granular duct cells of submandibular glands [7].
• After administration of alpha-isoproterenol, a beta-adrenergic stimulant, a large numbers of small secretory granules were present in the granular duct cells and an expansion of the rough endoplasmic reticulum in SMP30-wild type (WT) mice; in contrast, little change was observed in SMP30-KO mice [7].

Associations of Rgn with chemical compounds

• Senescence marker protein-30 (SMP30) is a calcium-binding protein that decreases in an androgen-independent manner with aging [3].
• Regucalcin (0.25 and 0.5 microM) had an inhibitory effect on liver nuclear phosphatase activity toward phosphotyrosine, phosphoserine, and phosphothreonine [8].
• Such an effect was significantly inhibited by the addition of trifluoperazine (2x10(-5) M), an antagonist of calmodulin, or staurosporine (10(-6) M), an inhibitor of protein kinase C. The present study demonstrates that endogenous regucalcin in rat brain neuronal cells has an inhibitory effect on Ca2+ dependent protein kinase activity [9].
• The addition of regucalcin (10(-9)-10(-7) M) in the enzyme reaction mixture caused a significant decrease in protein kinase activity in the absence of calmodulin or dioctanoylglycerol without Ca(2+) addition [9].
• SMP 30 expression was decreased initially, then increased along with hepatic regeneration, after carbon tetrachloride (CCl4) administration [10].

Regulatory relationships of Rgn

• Moreover, deletion of the SMP30 gene enhanced liver injury after treatment in vivo with anti-Fas antibody and the SMP30+/- mice showed intermediate susceptibility to Fas-induced apoptosis [3].

Other interactions of Rgn

• An enzyme-labeled antibody technique has demonstrated that SMP30 localized to the ducts (granular, intercalated, and striated ducts) of mouse submandibular glands [7].
• Of these, 14 protein spots including carbonic anhydrase III, senescence marker protein 30 and selenium binding protein 2 were differentially changed only in B6 mice, which was also confirmed in part by Western blotting [11].

Analytical, diagnostic and therapeutic context of Rgn

• Molecular cloning of the cDNA coding for regucalcin and its mRNA expression in mouse liver: the expression is stimulated by calcium administration [4].
• Northern blot analysis with the mouse liver cDNA probe revealed that mouse regucalcin mRNA was mainly present in the liver but only slightly in the kidney with a size of 1.8 kb [4].
• To elucidate the molecular mechanism of regulation of SMP30 gene expression we have cloned its gene promoter and carried out DNA-protein interaction analyses by DNase I footprinting and electrophoretic mobility shift assay [12].
• Therefore, we established a SMP30 deficient strain of mice with a C57BL/6 background by gene targeting to investigate whether this molecule is involved in renal tubular cell senescence [13].

References