Disease relevance of PTMA

• The purpose of the present investigation was to provide a better understanding of the role of PTMA in human prostate cancers [1].
• METHODS AND RESULTS: PTMA expression in 68 prostate cancer cases and in prostate cancer cell lines was examined by immunohistochemistry and immunoblotting, and its levels were increased with progression from normal epithelium, through prostatic intraepithelial neoplasia (PIN) to carcinomas, correlating with the Gleason's pattern [1].
• We isolated PTalpha, known to be a chromatin-remodeling protein associated with cell proliferation, using REA as bait in a yeast two-hybrid screen with a cDNA library from MCF-7 human breast cancer cells [2].
• In neuroblastoma cells, 17 beta-estradiol treatment induced a transient increase in the transcription of estrogen-responsive element-containing promoters including those regulating TGF-alpha and prothymosin alpha synthesis [3].
• Epstein-Barr virus nuclear antigen 3C and prothymosin alpha interact with the p300 transcriptional coactivator at the CH1 and CH3/HAT domains and cooperate in regulation of transcription and histone acetylation [4].

High impact information on PTMA

• Antiapoptotic function of RNA-binding protein HuR effected through prothymosin alpha [5].
• Regulation of apoptosis by the p8/prothymosin alpha complex [6].
• A differential expression of the two alpha-thymosins was observed in thymus (prothymosin alpha-rich) and liver (parathymosin alpha-rich) [7].
• A decline in the levels of both alpha-thymosins was found with age, with prothymosin alpha in thymus showing the sharpest change (15- to 30-fold) [7].
• In breast cancer, in particular, the mean increase for prothymosin alpha and parathymosin alpha was 17.9- and 11.5-fold, respectively [7].

Chemical compound and disease context of PTMA

• Conversely, inhibition of nuclear PTalpha expression in breast cancer cells using antisense methodology resulted in the inhibition of E2-induced breast cancer cell proliferation [8].
• Regulation of prothymosin alpha gene expression by estrogen in estrogen receptor-containing breast cancer cells via upstream half-palindromic estrogen response element motifs [9].
• Binding of human prothymosin alpha to the leucine-motif/activation domains of HTLV-I Rex and HIV-1 Rev [10].

Biological context of PTMA

• Further time course analysis of PTMA and Nip2 mRNAs levels indicated that the hormone exerted a marked biphasic regulatory effect on expression of both messages during the course of cell differentiation [11].
• A genomic clone encoding prothymosin alpha (gene symbol: PTMA), a nuclear-targeted protein associated with cell proliferation, was isolated and the 5'-regulatory region subcloned and sequenced [12].
• Knockdown of PTMA expression in PC3 cells by RNAi resulted in the inhibition of both cell growth and invasion in vitro [1].
• Previous studies have shown that EBNA3C interacts with p300 and prothymosin alpha (ProTalpha) in EBV-infected cells and may be involved in recruiting acetyltransferases to the chromatin for acetylation of histones and transcriptional activation [13].
• Analysis of the prothymosin alpha promoter and 5'-flanking region, and electrophoretic gel mobility shift studies showed the strong inducibility by the estradiol-ER complex to be mediated by two consensus half-palindromic estrogen response elements at -750 and -1051, which directly bind the ER [9].

Anatomical context of PTMA

• All cell lines studied (LNCaP, 22Rv1, DU145, and PC3) showed high PTMA expression compared with prostate epithelial cells (PrEC) [1].
• Marked differences in the expression of PTMA and Tim10 were observed during the differentiation of human primary skeletal muscle cells [14].
• Prothymosin alpha (PTMA), and translocase of inner mitochondrial membrane 10 (Tim10), two genes not previously implicated in RMS, showed reduced expression during differentiation [14].
• Prothymosin alpha mRNA is inducible; upon mitogen stimulation it increased greater than 15-fold above the level found in resting lymphocytes [15].
• Examination of mouse and human tissues revealed the presence of prothymosin alpha mRNA in kidney, liver, spleen, normal lymphocytes (predominantly T cells), human T-cell leukemia virus-infected T cells, and myeloma cells (B-cell lineage) [15].

Associations of PTMA with chemical compounds

• In particular, PTMA was found to accumulate at both 1 and 17 hr after E2 treatment, whereas P10 product accumulated only at 1 hr [11].
• Overall these studies underscore the importance of PTalpha in estrogen-induced breast cell proliferation [8].
• The largest permeant ion, tetramethylammonium with a diameter of 0.55 nm, had PTMA/PNa of 0.09 [16].
• Moreover, crystallization of the PTMA radical in presence of ethanol to form the beta phase of PTMA radical prevented the dimer formation; this resulted in the suppression of this interaction and provides further evidence of the magnetic exchange mechanism through noncovalent hydrogen bonds at long distances [17].
• Investigation of the transmission of magnetic interactions through hydrogen bonds has been carried out for two different benzoic acid derivatives which bear either a tert-butyl nitroxide (NOA) or a poly(chloro)triphenylmethyl (PTMA) radical moiety [17].

Physical interactions of PTMA

• Estrogenic stimulation of prothymosin alpha required a DNA binding form of ER with a functional activation function-2 domain [9].
• Prothymosin alpha interacts with the CREB-binding protein and potentiates transcription [18].

Regulatory relationships of PTMA

• Prothymosin alpha selectively enhances estrogen receptor transcriptional activity by interacting with a repressor of estrogen receptor activity [2].
• Prothymosin alpha (ProT) is regulated by c-Myc, an oncoprotein overexpressed in synovium of rheumatoid arthritis, and is associated with cell proliferation [19].
• Prothymosin alpha enhances interleukin 2 receptor expression in normal human T-lymphocytes [20].
• Overexpression of the oncoprotein prothymosin alpha triggers a p53 response that involves p53 acetylation [21].

Other interactions of PTMA

• Regulation of prothymosin alpha by estrogen receptor alpha: molecular mechanisms and relevance in estrogen-mediated breast cell growth [8].
• Increased nuclear expression of PTalpha is correlated with increased proliferation as measured by expression of Ki67 nuclear antigen [8].
• The distribution of prothymosin alpha in the nucleus is related to that of transcription sites, whereas the distribution of parathymosin correlates with early replication sites [22].
• In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity [21].
• The in vivo and in vitro data indicated that the prothymosin alpha-Keap1 interaction is direct, highly specific, and functionally relevant [23].

Analytical, diagnostic and therapeutic context of PTMA

• Radioimmunoassays specific for the N and C termini of human prothymosin alpha and the N terminus of human parathymosin alpha were employed for the measurement of the levels of alpha-thymosins in human thymus, spleen, and liver during normal growth and intestine and breast in malignant growth [7].
• The major cross-reacting peptide in human plasma detected with a radioimmunoassay (RIA) for thymosin alpha 1 was identified as prothymosin alpha, based on its elution properties in gel-filtration chromatography and its amino acid composition after purification by HPLC [24].
• Molecular cloning of cDNA for human prothymosin alpha [25].
• The immunoregulatory polypeptide prothymosin alpha and its biologically active N-terminal fragment thymosin alpha 1m, with relative molecular masses of 12,500 and 3108 respectively, were found to behave as oligomers (trimers to hexamers) in gel-filtration measurements [26].
• We demonstrate that at low pH ( approximately 3) and high concentrations, prothymosin alpha is capable of forming regular elongated fibrils with flat ribbon structure 4-5 nm in height and 12-13 nm in width as judged from scanning force and electron microscopy [27].

References