Alternative titles; symbols
HGNC Approved Gene Symbol: TMSB4X
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38): X:12,975,110-12,977,223 (from NCBI)
Thymosin-beta-4 induces the expression of terminal deoxynucleotidyl transferase activity in vivo and in vitro, inhibits the migration of macrophages, and stimulates the secretion of hypothalamic luteinizing hormone-releasing hormone (Clauss et al., 1991).
By differential screening of a cDNA library prepared from leukocytes of an acute lymphocytic leukemia patient, Gondo et al. (1987) isolated a cDNA encoding thymosin-beta-4. Using Northern blot analysis, they studied the expression of the 830-nucleotide thymosin-beta-4 mRNA in various primary myeloid and lymphoid malignant cell lines and in hemopoietic cell lines. Gondo et al. (1987) stated that the pattern of thymosin-beta-4 gene expression suggests that it may be involved in an early phase of the host defense mechanism.
Clauss et al. (1991) noted that the protein was originally isolated from a partially purified extract of calf thymus, thymosin fraction 5, which induced differentiation of T cells and was partially effective in some immunocompromised animals. Further studies demonstrated that the molecule is ubiquitous; it had been found in all tissues and cell lines analyzed. It is found in highest concentrations in spleen, thymus, lung, and peritoneal macrophages. Clauss et al. (1991) isolated a cDNA clone for the human interferon-inducible gene 6-26 (Friedman et al., 1984) and showed that its sequence was identical to that for the human thymosin-beta-4 gene.
Clauss et al. (1991) stated that rat thymosin-beta-4 is synthesized as a 44-amino acid propeptide which is processed into a 43-amino acid peptide by removal of the first methionyl residue. The molecule does not have a signal peptide. Human thymosin-beta-4 has a high degree of homology to rat thymosin-beta-4; the coding regions differ by only 9 nucleotides, and these are all silent base changes.
Li et al. (1996) established that in the mouse there is a single Tmsb4 gene and that the lymphoid-specific transcript is generated by extending the ubiquitous exon 1 with an alternate downstream splice site.
Li et al. (1996) stated that thymosin-beta-4 is an actin monomer sequestering protein that may have a critical role in modulating the dynamics of actin polymerization and depolymerization in nonmuscle cells. Its regulatory role is consistent with the many examples of transcriptional regulation of T-beta-4 and of tissue-specific expression. Lymphocytes have a unique T-beta-4 transcript relative to the ubiquitous transcript found in many other tissues and cells.
Lahn and Page (1997) determined that the TB4X gene escapes X inactivation, and suggested that it should be investigated as a candidate gene for Turner syndrome. See 400010.
Commenting on the use of high-density DNA microarrays in gene expression profiling, Ridley (2000) pointed out that the results of Clark et al. (2000) indicated that thymosin beta-4 is required for the metastasis of melanoma cells.
Bock-Marquette et al. (2004) demonstrated that the G-actin sequestering peptide thymosin beta-4 promoted myocardial and endothelial cell migration in the embryonic heart and retained this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta-4. Thymosin beta-4 formed a functional complex with PINCH1 (602567) and integrin-linked kinase (ILK; 602366), resulting in activation of the survival kinase AKT, also known as protein kinase B (164730). After coronary artery ligation in mice, thymosin beta-4 treatment resulted in upregulation of Ilk and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. Bock-Marquette et al. (2004) concluded that thymosin beta-4 promotes cardiomyocyte migration, survival, and repair.
By subtractive hybridization and real-time RT-PCR, Ji et al. (2003) found that TMSB4X was one of several genes whose expression was increased in nonsmall cell lung cancers prior to metastasizing. TMSB4X expression was associated with cancers in a stage- and histology-specific manner. Ji et al. (2003) suggested that TMSB4X expression may be a prognostic parameter for patient survival in stage I nonsmall cell lung cancer.
Smart et al. (2007) identified thymosin beta-4 as essential for all aspects of coronary vessel development in mice, and demonstrated that T-beta-4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells, and endothelial cells. T-beta-4 knockdown in the heart is accompanied by significant reduction in the proangiogenic cleavage product N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). Although injection of this cleavage product was unable to rescue T-beta-4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially-derived precursor cells. Smart et al. (2007) concluded that their study identifies T-beta-4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals T-beta-4-induced adult epicardial cells as a viable source of vascular progenitors for continued renewal of regressed vessels at low basal level or sustained neovascularization following cardiac injury.
In mice, Smart et al. (2011) demonstrated that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. Smart et al. (2011) revealed a novel genetic label of the activated adult progenitors via reexpression of a key embryonic epicardial gene, Wilms tumor-1 (WT1; 607102), through priming by thymosin beta-4, a peptide shown to restore vascular potential to adult epicardium-derived progenitor cells with injury. Cumulative evidence indicated an epicardial origin of the progenitor population, and embryonic reprogramming resulted in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labeled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. Smart et al. (2011) showed that derived cardiomyocytes are able to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represented a significant step towards resident cell-based therapy in human ischemic heart disease.
By use of a panel of human rodent somatic cell hybrids, Clauss et al. (1991) showed that the 6-26 cDNA, corresponding to the human thymosin-beta-4 gene, recognized 7 genes, members of a multigene family, present on chromosomes 1, 2, 4, 9, 11, 20, and X. These genes are symbolized TMSL1, TMSL2, etc., respectively.
By interspecific backcross mapping, Li et al. (1996) located the mouse gene, which they symbolized Ptmb4, to the distal region of the mouse X chromosome, linked to Btk (300300) and Gja6. Thus, the human gene could be predicted to reside on the X chromosome in the general region of Xq21.3-q22, where BTK is located. By analysis of somatic cell hybrids, Lahn and Page (1997) mapped the thymosin-beta-4, or TB4X, gene to the X chromosome. They noted that a homologous gene, TB4Y (400017), is present on the Y chromosome.
Bock-Marquette, I., Saxena, A., White, M. D., DiMaio, J. M., Srivastava, D. Thymosin beta-4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432: 466-472, 2004. [PubMed: 15565145] [Full Text: https://doi.org/10.1038/nature03000]
Clark, E. A., Golub, T. R., Lander, E. S., Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406: 532-535, 2000. Note: Erratum: Nature 411: 974 only, 2001. [PubMed: 10952316] [Full Text: https://doi.org/10.1038/35020106]
Clauss, I. M., Wathelet, M. G., Szpirer, J., Islam, M. Q., Levan, G., Szpirer, C., Huez, G. A. Human thymosin-beta-4/6-26 gene is part of a multigene family composed of seven members located on seven different chromosomes. Genomics 9: 174-180, 1991. [PubMed: 2004759] [Full Text: https://doi.org/10.1016/0888-7543(91)90236-8]
Friedman, R. L., Manly, S. P., McMahon, M., Kerr, I. M., Stark, G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38: 745-755, 1984. [PubMed: 6548414] [Full Text: https://doi.org/10.1016/0092-8674(84)90270-8]
Gondo, H., Kudo, J., White, J. W., Barr, C., Selvanayagam, P., Saunders, G. F. Differential expression of the human thymosin-beta(4) gene in lymphocytes, macrophages, and granulocytes. J. Immun. 139: 3840-3848, 1987. [PubMed: 3500230]
Ji, P., Diederichs, S., Wang, W., Boing, S., Metzger, R., Schneider, P. M., Tidow, N., Brandt, B., Buerger, H., Bulk, E., Thomas, M., Berdel, W. E., Serve, H., Muller-Tidow, C. MALAT-1, a novel noncoding RNA, and thymosin beta-4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22: 8031-8041, 2003. [PubMed: 12970751] [Full Text: https://doi.org/10.1038/sj.onc.1206928]
Lahn, B. T., Page, D. C. Functional coherence of the human Y chromosome. Science 278: 675-680, 1997. [PubMed: 9381176] [Full Text: https://doi.org/10.1126/science.278.5338.675]
Li, X., Zimmerman, A., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Yin, H. L. The mouse thymosin beta-4 gene: structure, promoter identification, and chromosome localization. Genomics 32: 388-394, 1996. [PubMed: 8838802] [Full Text: https://doi.org/10.1006/geno.1996.0133]
Ridley, A. Molecular switches in metastasis. Nature 406: 466-467, 2000. [PubMed: 10952292] [Full Text: https://doi.org/10.1038/35020170]
Smart, N., Bollini, S., Dube, K. N., Vieira, J. M., Zhou, B., Davidson, S., Yellon, D., Riegler, J., Price, A. N., Lythgoe, M. F., Pu, W. T., Riley, P. R. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474: 640-644, 2011. [PubMed: 21654746] [Full Text: https://doi.org/10.1038/nature10188]
Smart, N., Risebro, C. A., Melville, A. A. D., Moses, K., Schwartz, R. J., Chien, K. R., Riley, P. R. Thymosin beta-4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445: 177-182, 2007. [PubMed: 17108969] [Full Text: https://doi.org/10.1038/nature05383]