Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation

Abstract

The present study aimed to elucidate the function of AT motif-binding factor 1 (ATBF1) during neurogenesis in the developing brain and in primary cultures of neuroepithelial cells and cell lines (Neuro 2A and P19 cells). Here, we show that ATBF1 is expressed in the differentiating field in association with the neuronal differentiation markers β-tubulin and MAP2 in the day E14.5 embryo rat brain, suggesting that it promotes neuronal differentiation. In support of this, we show that ATBF1 suppresses nestin expression, a neural stem cell marker, and activates the promoter of Neurod1 gene, a marker for neuronal differentiation. Furthermore, we show that in Neuro 2A cells, overexpressed ATBF1 localizes predominantly in the nucleus and causes cell cycle arrest. In P19 cells, which formed embryonic bodies in the floating condition, ATBF1 is mainly cytoplasmic and has no effect on the cell cycle. However, the cell cycle was arrested when ATBF1 became nuclear after transfer of P19 cells onto adhesive surfaces or in isolated single cells. The nuclear localization of ATBF1 was suppressed by treatment with caffeine, an inhibitor of PI(3)K-related kinase activity of ataxa-telangiectasia mutated (ATM) gene product. The cytoplasmic localization of ATBF1 in floating/nonadherent cells is due to CRM1-dependent nuclear export of ATBF1. Moreover, in the embryonic brain ATBF1 was expressed in the cytoplasm of proliferating stem cells on the ventricular zone, where cells are present at high density and interact through cell-to-cell contact. Conversely,in the differentiating field, where cell density is low and extracellular matrix is dense, the cell-to-matrix interaction triggered nuclear localization of ATBF1, resulting in the cell cycle arrest. We propose that ATBF1 plays an important role in the nucleus by organizing the neuronal differentiation associated with the cell cycle arrest.

Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer

“…40,41 Association with CRM1, an exportin, might be another important molecular mechanism that regulates the nucleus-cytoplasm transfer of ATBF1. 20 In conclusion, we have revealed that ATBF1 in the nucleus negatively regulates the MUC5AC gene in gastric cancer by binding to an AT motif-like element in the MUC5AC promoter.…”

“…19 Thus, not only the expression levels of ATBF1, but also its subcellular localization, appear to be linked to cell differentiation and induction of cell cycle arrest. 20 The present study of mucin expression in gastric cancer and the functions of ATBF1 [21][22][23] has revealed that the expression of ATBF1 in the nucleus suppresses MUC5AC expression in gastric cancer. This is the first report to document the molecular mechanism of altered expression of MUC5AC, as regulated by ATBF1, in gastric cancer.…”

“…The ATM signaling should be involved in the nuclear localization of ATBF1. 20 Two nuclear-localizing signals (NLS) exist in exon 9, which are frequently deleted in cancer cells by alternative splicing. 19 The subcellular localization of ATBF1 may reflect the variation of its structure like other transcription factors such as ING4 and BRCA1.…”

Atbf1 is required for the Pit1 gene early activation

“…Atbf1 has been reported to exert roles in control of cell proliferation (24). Although Atbf1 gene-trap mutants failed to display overt defect in cell proliferation in early pituitary development, it remains possible that a trace amount of wt Atbf1 protein may adequately function to regulate subsets of its targets, whereas Pit1 ⌭⌭␣ would be particularly sensitive to Atbf1 levels.…”

Evaluation of novel SNPs and haplotypes within the <i>ATBF1</i> gene and their effects on economically important production traits in cattle

“…Xu et al: Evaluation of novel SNPs and haplotypes within the ATBF1 gene mor suppressor in several cancers (Kawaguchi et al, 2016;Sun et al, 2014Sun et al, , 2015. More importantly, it plays an important role in regulating myogenesis, adipose tissue development and transactivating the cell cycle inhibitor (Jung et al, 2005;Dean, 1997, 1999;Richard and Stephens, 2014).…”