Disease relevance of TMPO

• We treated two patients affected by DiGeorge syndrome with long-term administration of the synthetic thymic hormone thymopoietin (TP5) [1].
• Effect of thymopoietin and interleukin 2 on depressed mitogenic responsiveness and colony formation of lymphocytes from patients with preleukemia [2].
• Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin [3].
• Latency-active promoter 2 (LAP 2) is a TATA-less promoter in herpes simplex virus type 1 (HSV-1) that can express genes during viral latency [4].
• Tpo and anti-AChR antibodies could participate together in the inhibition of neuromuscular conduction with Tpo modulating the depressive effect of the antibodies on the neuromuscular junction in myasthenia gravis [5].

High impact information on TMPO

• Differentiation of lymphoid precursor cells in a variety of species is induced by polypeptide hormones such as thymopoietin for T cells and bursin for B cells [6].
• These inducing properties of bursin are the reverse of the inducing properties of thymopoietin produced by the thymus and are appropriate to a physiological B-cell-inducing hormone [6].
• HA95-LAP2 beta interaction is not required for NE formation [7].
• We propose that an interaction of LAP2beta, or LAP2 proteins, with HA95 is involved in the control of initiation of DNA replication [7].
• Solution structure of the constant region of nuclear envelope protein LAP2 reveals two LEM-domain structures: one binds BAF and the other binds DNA [8].

Chemical compound and disease context of TMPO

• The cell lines derived from the single squamous cell carcinoma and the two adenocarcinomas expressed the PD-ECGF/TP mRNA, and were found to have the corresponding protein both in cell lysates and conditioned media as determined both by immunoblotting and measurement of thymidine phosphorylase activity [9].
• Eight patients with cutaneous T-cell lymphomas (6 patients with mycosis fungoides, 1 patient with Sézary's syndrome, 1 patient with low-grade malignant lymphoma, unclassified) were treated with TP-5, a synthetic pentapeptide having the same biologic activity as the thymic hormone thymopoietin [10].
• U46619-induced phosphorylation of ERK1/2 at 5 min was inhibited by pertussis toxin in both cells, suggesting that G(i) is involved in the phosphorylation mediated via both TP isoforms [11].

Biological context of TMPO

• The human TMPO gene maps to chromosome band 12q22 [12].
• The eight exons of the TMPO gene are spread over approximately 35 kb [12].
• Sequence scanning of overlapping cosmids has identified three additional genes, TMPO, LDHB and KCNA1, which map to human chromosome 12, with the latter two mapping to 12p12-11 [13].
• Isolation and complete amino acid sequence of human thymopoietin and splenin [14].
• Injection of the lamin-binding region of rat LAP2 into early G1 phase HeLa cells also strongly affects nuclear growth; it almost completely prevents the threefold nuclear volume increase that normally occurs during the ensuing 10 h [15].

Anatomical context of TMPO

• TMPO alpha is present diffusely throughout the nucleus, while TMPOs beta and gamma are localized to the nuclear membrane [12].
• Here we report on the demonstration of putative human TMPOdelta and epsilon by immunoblotting of human cell lines using a newly prepared polyclonal antiserum against the common N-terminal region of TMPO [16].
• At least three LAP2 isoforms are identified in normal and neoplastic thyroid [17].
• Since the lamin-binding fragment of LAP2 most likely acts by inhibiting dynamics of the nuclear lamina, our results suggest that a normal function of LAP2 involves regulation of nuclear lamina growth [15].
• Thymopoietin (TP) was originally isolated as a 5-kDa 49-aa protein from bovine thymus in studies of the effects of thymic extracts on neuromuscular transmission and was subsequently observed to affect T-cell differentiation and function [18].

Associations of TMPO with chemical compounds

• Analogous experiments with 3,3,5,5-tetramethyl-1-pyrroline N-oxide (TMPO) led only to the trapping of alkoxyl radicals with no evidence for peroxyl radical adducts, this is presumably due to a decreased rate of radical addition because of increased steric hindrance [19].
• (C5Me5)3Sm reacts with the free radical 2,2,6,6-tetramethylpiperidinyl-1-oxy (TMPO) to form (C5Me5)2 and the per nitroxide [(eta 1-ONC5H6Me4)2Sm(mu-eta 1:eta 2-ONC5H6Me4)]2 [20].
• The effect of myoglobin on the stability of the hydroxyl-radical adducts of 5,5 dimethyl-1-pyrolline-N-oxide (DMPO), 3,3,5,5 tetramethyl-1-pyrolline-N-oxide (TMPO) and 1-alpha-phenyl-tert-butyl nitrone (PBN) in the presence of hydrogen peroxide [21].
• Hydrogen peroxide readily converts myoglobin to its ferryl (FeIV) derivative, and this centre may be responsible for the oxidation of the DMPO and TMPO adducts [21].
• In contrast, we found that the portion of LAP2 involved in binding to chromosomes resides in a separate region of the protein near its NH2 terminus [22].

Physical interactions of TMPO

• Lamina-associated polypeptide 2 (LAP2) is an integral membrane protein of the inner nuclear membrane that binds to both lamin B and chromatin and has a putative role in nuclear envelope (NE) organization [15].

Regulatory relationships of TMPO

• Lamin-binding fragment of LAP2 inhibits increase in nuclear volume during the cell cycle and progression into S phase [15].

Other interactions of TMPO

• The nuclear envelope proteins LAP2, emerin and MAN1 share a conserved approximately 40-residue 'LEM' motif [8].
• While lamin B is cleaved by caspase 6, the protease responsible for the cleavage of LAP2 and Nup153 was probably caspase 3, since (1) cleavage of both proteins was specifically prevented by in vivo addition of caspase 3 inhibitor Ac-DEVD-CHO and (2) consensus sites for these caspases are present in both proteins [23].
• In these studies, protein LAP2/thymopoietin beta, another marker of the inner nuclear membrane, was segregating as lamin B receptor, suggesting that both proteins were contained in the same mitotic vesicles [24].
• Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy [25].
• Thymic epithelium from three patients with severe cellular immunodeficiency diseases were compared with age-matched normal thymic epithelium using three markers of human thymic epithelium and antibodies against thymosin alpha 1, thymopoietin, and thymosin beta 4 [26].

Analytical, diagnostic and therapeutic context of TMPO

• This effect appears to be specifically due to lamin binding, because it also is caused by microinjection of the minimal lamin-binding region of LAP2 (residues 298-373) but not by the chromatin-binding domain (residues 1-88) [15].
• Bioassay determinations of thymopoietin and thymic hormone levels in human plasma [27].
• A polyclonal rabbit anti-bovine thymopoietin antiserum was used to develop a radioimmunoassay and sandwich enzyme-linked immunosorbent (ELISA) assay for the thymic hormone thymopoietin [28].
• Similar approaches are being pursued to develop an immunoassay for thymopoietin in human serum [28].
• A total of 113 subjects from 88 families (56 with familial DCM (FDC) and 32 with sporadic DCM) were screened for LAP2 mutations using denaturing high-performance liquid chromatography and sequence analysis [25].

References