Disease relevance of TMSB4X

• Up-regulation of thymosin beta4 was also found in ras-transformed fibroblasts and metastatic human melanoma cells [1].
• A cDNA clone encoding human thymosin-beta 4 was isolated from a cDNA library prepared from peripheral blood leukocytes of a patient with acute lymphocytic leukemia [2].
• Overexpression of the thymosin beta-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma [3].
• Thymosin beta-4 (Tbeta-4) is the major actin-sequestering protein that has been shown to be upregulated in a wide variety of human carcinomas and has been implicated to be involved in altering the motility of certain tumors [3].
• Among leukemic cell samples obtained from leukemia patients, the T beta 4 gene was highly expressed in a lymphoid lineage, especially in adult T-cell leukemia (ATL) cells, rather than in a granulocyte lineage [4].
• Advantages such as immune evasion and resistance to anticancer drug-induced apoptosis acquired by colon cancer cells through Tbeta4 overexpression might facilitate their survival during metastasis and chemotherapy [5].

High impact information on TMSB4X

• How profilin promotes actin filament assembly in the presence of thymosin beta 4 [6].
• Thymosin beta 4 is a major actin monomer binding protein present at high concentration in many vertebrate cells and cell lines [7].
• The actin binding site of thymosin beta 4 mapped by mutational analysis [8].
• Thymosin beta 4 (beta 4) is a 5-kDa polypeptide originally identified in calf thymus [9].
• We have found that T beta 4 upregulates the expression of plasminogen activator inhibitor 1 (PAI-1) in endothelial cells measured both at the level of mRNA and protein synthesis [10].

Chemical compound and disease context of TMSB4X

• The FX electron acceptor in Photosystem I (PS I) is a highly electronegative (Em = -705 mV) interpolypeptide [4Fe-4S] cluster ligated by cysteines 556 and 565 on PsaB and cysteines 574 and 583 on PsaA in Synechocystis sp. PCC 6803 [11].
• Basal levels of thymosin beta 4 were similar in normal women during the early follicular phase, women with premature ovarian failure, postmenopausal women not receiving estrogen, and individuals with gonadal dysgenesis [12].
• Therapeutic Potential of Thymosin-beta4 and its Derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in Cardiac Healing After Infarction [13].

Biological context of TMSB4X

• Reduction of thymosin beta4 and actin in HL60 cells during apoptosis is preceded by a decrease of their mRNAs [14].
• To further elucidate if the changes of thymosin beta4 and actin content correlate with the gene expression the relative mRNA content of thymosin beta4 and beta-actin was determined using the ribonuclease protection assay (RPA) [14].
• Assignment of the thymosin beta 4 X/Y chromosome (TMSB4X/Y) gene to tammar wallaby chromosome 5p by fluorescence in situ hybridisation [15].
• Up-regulation of the actin sequestering molecule thymosin beta4 was the most prominent change in both cell lines [1].
• Additional experiments using subcutaneously implanted Matrigel showed that T beta 4 stimulated cell migration in vivo [16].

Anatomical context of TMSB4X

• Thymosin beta 4 induces the synthesis of plasminogen activator inhibitor 1 in cultured endothelial cells and increases its extracellular expression [10].
• T beta 4 has been identified as a factor involved in the differentiation of human umbilical vein endothelial cells (HUVECs) cultured on Matrigel [16].
• Thymosin beta4 is a determinant of the transformed phenotype and invasiveness of S-adenosylmethionine decarboxylase-transfected fibroblasts [1].
• Of the primary cell types tested, only human coronary artery cells responded to T beta 4 treatment, suggesting that the migration activity of T beta 4 was endothelial cell-specific [16].
• T beta 4 treatment also increased the production of matrix metalloproteinases that may degrade the basement membrane during angiogenesis [16].

Associations of TMSB4X with chemical compounds

• In contrast, significant amounts of AGP were found to be associated with the cells overexpressing enhanced green fluorescent protein (EGFP)-alpha1-acid glycoprotein (AGP) without Tbeta4 treatment [17].
• Therefore we studied changes in thymosin beta4 and actin content of HL60 cells after induction of apoptosis using cytosine arabinoside (araC) [14].
• Interestingly, a sponge toxin, latrunculin A, which inhibits the binding of thymosin beta4 to actin, was found to profoundly affect the morphology and proliferation of the AdoMetDC transformants and to block their invasion in three-dimensional Matrigel [1].
• At least 50% of the actin in resting human platelets is unpolymerized, and the bulk of this unpolymerized actin is complexed with a recently identified acidic, heat-stable 5-kDa peptide, named "Fx." Purified Fx binds stoichiometrically to muscle G-actin, forming a complex identifiable by nondenaturing polyacrylamide gel electrophoresis [18].
• We further showed that in digitonin permeabilised and extracted cells, fluorescent thymosin beta4 was solely localised within the cytoplasm, whereas it was found concentrated within the cell nuclei after an additional Triton X100 extraction [19].

Physical interactions of TMSB4X

• Taken together, these results provide the evidence supporting a novel mechanism by which active PAI-1 can be bound to the Tbeta4-activated endothelial cells, thus influencing their adhesive properties as well as their ability to generate plasmin [17].
• Furthermore, T beta 4 enhanced c-Fos/c-Jun DNA-binding activity to the activator protein 1 (AP-1)-like element (-59 to -52) [10].

Regulatory relationships of TMSB4X

• Binding of PAI-1 to endothelial cells stimulated by thymosin beta4 and modulation of their fibrinolytic potential [17].
• In this study, thymosin beta4 was found to be differentially expressed in HGF-treated HUVECs compared with control [20].
• Zyxin is upregulated in the nucleus by thymosin beta4 in SiHa cells [21].
• It was previously shown that the N-fragment (1-4) of thymosin beta 4 (Ac-Ser-Asp-Lys-Pro-OH) inhibits in vivo the entry of cell populations into S-phase [22].
• We propose that DFMO reduces migration by interfering with the sequestration of G-actin by Tbeta4 and the association of F-actin with activated EGF receptors [23].

Other interactions of TMSB4X

• PAI-1 did not bind to quiescent cells but only to the Tbeta4-activated endothelial cells [17].
• Already after 24 h the relative amount of mRNA of thymosin beta4 and beta-actin was greatly reduced to 71 and 58%, respectively [14].
• A marked increase on the invasiveness in Tbeta-4-overexpressing SW480 cells with increased levels and activity of matrix metalloproteinase-7 (MMP-7) was observed [3].
• These results suggest that upregulation of Tbeta-4, by promoting the disruption of cell-cell adhesion and a consequential activation of the beta-catenin signaling, could be a key event in the acquisition of growth advantages as well as invasive phenotypes in human colorectal carcinomas [3].
• Furthermore, the levels of Fas as well as the susceptibility to Fas ligand-mediated apoptosis in Tbeta-4-overexpressing cells were significantly decreased [3].

Analytical, diagnostic and therapeutic context of TMSB4X

• Northern blot analyses of different neoplastic B lymphocytes revealed that steady state levels of thymosin-beta 4 mRNA varied as a function of differentiation stage [2].
• Here we show that after microinjection into intact cells, fluorescently labelled thymosin beta4 has a diffuse cytoplasmic and a pronounced nuclear staining [19].
• Thymosin beta4 has been previously reported to localise intracellularly to the cytoplasm as detected by immunofluorescence [19].
• Circular dichroism data indicate that free thymosin beta 4 is predominantly unstructured, containing at most six residues of alpha-helix, and that up to six additional residues may adopt an alpha-helical conformation upon binding actin [24].
• Data from HPLC profile and induction of MMPs indicate that HGF may affect the biological behavior of HUVECs through a combination of the direct effects of HGF itself and indirect effects mediated via induction of thymosin beta4 in vitro [20].

References