Regulation of prothymosin α by estrogen receptor α: molecular mechanisms and relevance in estrogen-mediated breast cell growth

Abstract

Prothymosin a (PTa) is a small highly acidic protein found in the nuclei of virtually all mammalian tissues. Its high conservation in mammals and wide tissue distribution suggest an essential biological role. While the exact mechanism of action of PTa remains elusive, the one constant has been its relationship with the proliferative state of the cell and its requirement for cellular growth and survival. Recently PTa was found to promote transcriptional activity by sequestering the anticoactivator, REA from the Estrogen Receptor (ER) complex. We now report that Estradiol (E 2 ) upregulates PTa mRNA and protein expression. Further studies indicate that ERa regulates PTa gene transcriptional activity. We have also delimited the region of PTa gene promoter involved in ERa-mediated transcriptional regulation and identified a novel ERabinding element. Increased intracellular PTa expression in the presence of estrogens is accompanied by increased nuclear/decreased cytoplasmic localization. Increased nuclear expression of PTa is correlated with increased proliferation as measured by expression of Ki67 nuclear antigen. Conversely, inhibition of nuclear PTa expression in breast cancer cells using antisense methodology resulted in the inhibition of E 2 -induced breast cancer cell proliferation. Overall these studies underscore the importance of PTa in estrogen-induced breast cell proliferation.

Contaminating cells alter gene signatures in whole organ versus laser capture microdissected tumors: a comparison of experimental breast cancers and their lymph node metastases

“…These genes may represent the best targets for further studies to identify the mechanisms that contribute to the spread or growth of breast cancer cells into and within LNs. Prothymosin alpha (PTMA) was increased in the LN metastases and has previously been shown to increase proliferation rates of breast cancer cells [18]. This finding is interesting in view of our previous findings of increased proliferation rates in LN metastases [11].…”

Identification of prothymosin-α1, the necrosis–apoptosis switch molecule in cortical neuronal cultures

“…It is generally thought to be an oncoprotein that is correlated with cell proliferation by sequestering anticoactivator, a repressor of estrogen receptor activity, in various cells (Martini et al, 2000; Bianco and Montano, 2002). On the other hand, ProTα has also been reported to act as an extracellular signaling molecule, as observed in the activation of macrophages, natural killer cells, and lymphokine-activated killer cells, and in the production of interleukin-2 and TNF-α (Pineiro et al, 2000).…”

Thymus hormones as prospective anti-inflammatory agents

“…Interrelations between endocrine circuits and thymosin-a are bi-directional. Thus, corticosteroids decrease the production of thymosin-a by thymic epithelial cells [62], but the sex hormone estradiol augments the expression of pro-thymosin-a [63]. The available data are summarized on Figure 1B.…”