Disease relevance of TMBIM4

• Radioimmunoassay studies were done to assess the amount of Z protein in controls and in various liver diseases [1].
• In contrast, both serum and hepatic Z protein concentrations were decreased in cases of constitutional hyperbilirubinemia [1].
• In cases of acute and chronic hepatitis, hepatic Z protein concentrations were generally decreased, whereas serum Z protein concentrations were increased [1].
• Positive staining by a peroxidase-antiperoxidase technique for detection of intracellular Z-protein was observed in 2 of 2 cardiac rhabdomyomas, 5 of 5 leiomyomas, 9 of 10 leiomyosarcomas, and in 15 of 18 rhabdomyosarcomas including 5 of 5 of the pleomorphic type, 7 of 9 of the embryonal type, and 3 of 4 of the alveolar type [2].
• RAZ, by limiting the availability of Z protein, is likely to modulate EBV reactivation [3].

High impact information on TMBIM4

• Once folded, however, the native Z protein shows substantial stability towards urea and incubation at 37 degrees C. The folding defect in Z antitrypsin leads to accumulation of an intermediate and it is the intermediate rather than the native protein which has a high tendency to aggregate [4].
• A carbohydrate chain could be prevented from attaching to the Z type either because of a conformational change or because of the replacement of a carbohydrate-binding asparagine residue in the Z protein [5].
• It is proposed that the Z protein lacks a carbohydrate chain with two terminal sialic acid residues [5].
• This interaction requires the coiled-coil dimerization domain of the Z protein and the carboxy-terminal portion of p53 [6].
• The Z protein, which has homology to the basic leucine zipper protein c-Fos, transactivates the promoters of several replicative cycle proteins [7].

Biological context of TMBIM4

• A low molecular weight binding protein for organic anions (Z protein) from human hepatic cytosol: purification and quantitation [1].
• In addition to Glu342 to Lys342 mutation in exon V which has been previously identified by peptide analysis, another point mutation (GTG to GCG in exon III) in the gene sequence predicts a second amino acid substitution (Val213 to Ala213) in the Z protein [8].
• Z protein downregulated replicon activity close to background levels [9].
• Our results suggest that the Z protein is required for both mRNA and genome synthesis, but in somewhat different manners [10].
• The latter represents a second amino acid substitution in the Z protein [11].

Anatomical context of TMBIM4

• Liver injury is caused by the accumulation of alpha(1)-AT mutant Z protein in hepatocytes, which triggers downstream intracellular injury pathways [12].
• Immunofluorescence studies revealed that Z protein was localized in the cytoplasm of hepatocytes, proximal tubular epithelium, and epithelial cells of the small intestine [1].
• The highest concentrations of Z protein were found in the liver, kidney, heart muscle, and small intestine, in that order [1].
• The normal M variant of alpha 1-antitrypsin is synthesised and secreted by Xenopus oocytes, the abnormal Z protein is not secreted and an intracellular form accumulates in the oocytes [13].
• We examined S1R expression in human breast cancer and assessed the activity of S1R ligands in breast cancer cell lines [14].

Associations of TMBIM4 with chemical compounds

• Human serum albumin had a higher affinity for bilirubin than did Z protein [1].
• In the presence of tunicamycin an unglycosylated form of M alpha 1-antitrypsin appears in the incubation medium but no corresponding unglycosylated version of the Z protein is secreted [13].
• Binding of bile acids, oleic acid, and organic anions by rat and human hepatic Z protein [15].
• The non-specific S1R ligands haloperidol, reduced haloperidol and progesterone produced a dose-dependent inhibition of the growth at high (>10 microM) concentrations [14].
• Using thioflavine T fluorescence and turbidity assays we demonstrated that the rate of aggregation for the Z AAT in the presence of LA at a molar ratio of 1:5 AAT to LA, in Tris-buffered saline, pH 7.4, is at least twice that of the Z protein alone or the M variant with and without LA [16].

Other interactions of TMBIM4

• Mutational analysis of the Z protein revealed that, in addition to all three functional domains of Z (dimerization domain, DNA binding domain, and activation domain), the carboxyl terminal 17 amino acids which stabilize the Z protein were necessary for induction of MMP9 expression [17].
• We found that SUMO-1 modification of Z has no apparent effect upon the stability and localization of the Z protein [18].
• The presence of desmin and Z-protein strongly suggests the myogenic character of this tumor [19].
• Liver fatty acid binding protein (L-FABP), a cytoplasmic 14 kDa protein previously termed Z protein, is conventionally considered to be an intracellular carrier of fatty acids in rat hepatocytes [20].
• The biologic t1/2 of both M and Z protein in the circulation were similar, averaging 71 hr for M protein and 80 hr for Z protein [21].

Analytical, diagnostic and therapeutic context of TMBIM4

• This lineage was found to have alpha 1-Pi-induced liver pathology in the neonatal period, concomitant with the accumulation of human Z protein in diastase-resistant cytoplasmic globules that could be revealed in the Periodic acid-Schiff reaction (PAS) [22].
• MDA-MB-361, MDA-MB-435, BT20 and MCF7 cells all expressed S1R protein by Western blot [14].
• Accumulation of Z protein has also been demonstrated by immunocytochemistry [23].
• S1R expression was neither a prognostic nor a predictive factor for efficacy of adjuvant chemotherapy but the study only included 58 cancer patients and therefore the statistical power is limited [14].
• The S1R-specific ligand, SKF 10047 demonstrated the least growth inhibitory activity and showed no interaction with chemotherapy [14].

References