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PubMed2001

The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis.

The mammalian ATF/CREB family of transcription factors represents a large group of basic region-leucine zipper (bZip) proteins which was originally defined in the late 1980s by their ability to bind to the consensus ATF/CRE site 'TGACGTCA'. Over the past decade, cDNA clones encoding identical or homologous proteins have been isolated by different laboratories and given different names. These proteins can be grouped into subgroups according to their amino acid similarity. In this review, we will briefly describe the classification of these proteins with a historical perspective of their nomenclature. We will then review three members of the ATF/CREB family of proteins: ATF3, ATF4 and ATF6. We will address four issues for each protein: (a) homologous proteins and alternative names, (b) dimer formation with other bZip proteins, (c) transcriptional activity, and (d) potential physiological functions. Although the name Activating Transcription Factor (ATF) implies that they are transcriptional activators, some of these proteins are transcriptional repressors. ATF3 homodimer is a transcriptional repressor and ATF4 has been reported to be either an activator or a repressor. We will review the reports on the transcriptional activities of ATF4, and propose potential explanations for the discrepancy. Although the physiological functions of these proteins are not well understood, some clues can be gained from studies with different approaches. When the data are available, we will address the following questions. (a) How is the expression (at the mRNA level or protein level) regulated? (b) How are the transcriptional activities regulated? (c) What are the interacting proteins (other than bZip partners)? (d) What are the consequences of ectopically expressing the gene (gain-of-function) or deleting the gene (loss-of-function)? Although answers to these questions are far from being complete, together they provide clues to the functions of these ATF proteins. Despite the diversity in the potential functions of these proteins, one common theme is their involvement in cellular responses to extracellular signals, indicating a role for these ATF proteins in homeostasis.

Activating Transcription Factor 2↗
PubMed1987

A cellular protein, activating transcription factor, activates transcription of multiple E1A-inducible adenovirus early promoters.

We have examined the relationship between sequence-specific DNA-binding proteins that activate transcription of E1A-inducible adenovirus early promoters. Factors previously referred to as E4F1 and E2A-EF bind to the E4 and E2A promoters, respectively. We demonstrate here that E4F1 and E2A-EF have identical DNA-binding specificity. Moreover, E4F1 and E2A-EF both activate transcription of the E4 and E2A promoters in vitro. These findings demonstrate that E4F1 and E2A-EF are the same factor, which we have designated activating transcription factor, or ATF. In addition to the E4 and E2A promoters, ATF binds to an important functional element of the E1A-inducible E3 promoter. Interaction of a common activator protein, ATF, with multiple E1A-inducible early viral promoters, suggests a significant role for ATF in E1A-mediated transcriptional activation.

Adenovirus Early Proteins↗
PubMed2006

The expression of transcription factor activating transcription factor 3 in the human prostate and its regulation by androgen in prostate cancer.

PURPOSE: ATF3 is a member of the basic leucine zipper/cyclic adenosine monophosphate responsive element binding protein family of transcription factors. There is overwhelming evidence that it is a stress inducible factor acting in a signal-type and cell-type dependent manner, and it is involved in cell proliferation and survival. We found that ATF3 was differently expressed in an in vitro prostate cancer tumor progression model and we investigated the possible role of ATF3 in prostate cancer. MATERIALS AND METHODS: ATF3 up-regulation in vivo/in vitro and androgen regulation were assessed by immunohistochemistry and immunoblot analysis. Results after forced ATF3 transfection were evaluated by proliferation assay and cell cycle analysis. RESULTS: Immunohistochemistry and immunoblot analysis revealed ATF3 up-regulation in prostate cancer in vitro and in vivo, and stimulation of expression by androgens. Antiandrogen treatment decreased ATF3 expression in androgen sensitive cells but acted as a stimulator in long-term androgen ablated cells representing a model for therapy refractory disease. Expression in tumors increased with higher Gleason scores and highest expression was observed in samples of therapy refractory tumor tissue. Forced ATF3 over expression in a prostate cancer cell line induced cell proliferation and accelerated cell cycle progression from G1 to S-phase. CONCLUSIONS: These data provide new insight into the role of ATF3 in prostate cancer development and/or progression. They indicate that ATF3 is an androgen regulated gene that is highly expressed in prostate tumors and stimulating cell proliferation. It represents a possible target for prostate cancer therapy.

Activating Transcription Factor 3↗
PubMed2006

Development of a fluorescent microsphere-based multiplexed high-throughput assay system for profiling of transcription factor activation.

Transcription factors (TFs), which play crucial roles in the regulation of gene expression in the human genome, are highly regulated by a variety of mechanisms. A single extracellular stimulus can trigger multiple signaling pathways, and these in turn can activate multiple TFs to mediate the inducible expression of target genes. Alterations in the activities of TFs are often associated with human diseases, such as altered activating factor 1, estrogen receptor, and p53 function in cancer, nuclear factor kappaB in inflammatory diseases, and peroxisome proliferator-activated receptor gamma in obesity. A systematic assay for profiling the activation of TFs will aid in elucidating the mechanisms of TF activation, reveal altered TFs associated with human diseases, and aid in developing assays for drug discovery. Here, we developed a 24-plex fluorescent microsphere-based TF activation assay system with a 96-well plate format. The assay system enabled high-throughput profiling of the DNA binding activity of TFs in multiple samples with high sensitivity.

DNA↗
PubMed1989

Identification and purification of a Saccharomyces cerevisiae protein with the DNA binding specificity of mammalian activating transcription factor.

Activating transcription factor (ATF) is a mammalian transcriptional activator, which is involved in the expression of many viral E1a-inducible and cellular cAMP-inducible genes. Here we identify from the yeast Saccharomyces cerevisiae a previously uncharacterized protein whose DNA binding specificity is like mammalian ATF. We purify this protein (yATF) and show that it is a 66-kDa polypeptide. Finally, we demonstrate that a mammalian ATF site can function as an upstream activating sequence in S. cerevisiae. Taken together, our results suggest that yATF is a previously uncharacterized S. cerevisiae transcriptional activator.

Activating Transcription Factors↗
PubMed2005

Mutated yeast heat shock transcription factor activates transcription independently of hyperphosphorylation.

The homotrimeric heat shock transcription factor (HSF) binds to the heat shock element of target genes and regulates transcription in response to various stresses. The Hsf1 protein of Saccharomyces cerevisiae is extensively phosphorylated upon heat shock; a modification that is under positive regulation by its C-terminal regulatory domain (CTM). Hyperphosphorylation has been implicated in gene-specific transcriptional activation. Here, we surveyed genes whose heat shock response is reduced by a CTM mutation. The CTM is indispensable for transcription via heat shock elements bound by a single Hsf1 trimer but is dispensable for transcription via heat shock elements bound by Hsf1 trimers in a cooperative manner. Intragenic mutations located within or near the wing region of the winged helix-turn-helix DNA-binding domain suppress the temperature-sensitive growth phenotype associated with the CTM mutation and enable Hsf1 to activate transcription independently of hyperphosphorylation. Deletion of the wing partially restores the transcriptional defects of the unphosphorylated Hsf1. These results demonstrate a functional link between hyperphosphorylation and the wing region and suggest that this modification is involved in a conformational change of a single Hsf1 trimer to an active form.

Base Sequence↗
PubMed1998

A hydrophobic segment within the 81-amino-acid domain of TFIIIA from Saccharomyces cerevisiae is essential for its transcription factor activity.

Transcription factor IIIA (TFIIIA) binds to the internal control region of the 5S RNA gene as the first step in the in vitro assembly of a TFIIIB-TFIIIC-TFIIIA-DNA transcription complex. An 81-amino-acid domain that is present between zinc fingers 8 and 9 of TFIIIA from Saccharomyces cerevisiae is essential for the transcription factor activity of this protein (C. A. Milne and J. Segall, J. Biol. Chem. 268:11364-11371, 1993). We have monitored the effect of mutations within this domain on the ability of TFIIIA to support transcription of the 5S RNA gene in vitro and to maintain cell viability. TFIIIA with internal deletions that removed residues 282 to 315, 316 to 334, 328 to 341, or 342 to 351 of the 81-amino-acid domain retained activity, whereas TFIIIA with a deletion of the short leucine-rich segment 352NGLNLLLN359 at the carboxyl-terminal end of this domain was devoid of activity. Analysis of the effects of double and quadruple mutations in the region extending from residue 336 to 364 confirmed that hydrophobic residues in this portion of the 81-amino-acid domain, particularly L343, L347, L354, L356, L357, and L358, and to a lesser extent F336 and L337, contributed to the ability of TFIIIA to promote transcription. We propose that these hydrophobic residues play a role in mediating an interaction between TFIIIA and another component of the transcriptional machinery. We also found that TFIIIA remained active if either zinc finger 8 or zinc finger 9 was disrupted by mutation but that TFIIIA containing a disruption of both zinc finger 8 and zinc finger 9 was inactive.

Amino Acid Sequence↗
PubMed2001

Effects of glia maturation factor overexpression in primary astrocytes on MAP kinase activation, transcription factor activation, and neurotrophin secretion.

Using the replication-defective adenovirus vector, we overexpressed rat glia maturation factor (GMF) in primary astrocyte cultures derived from embryonic rat brains. Among the three isoforms of MAP kinase, there was a big increase in the phosphorylation of p38, as detected with Western blotting using the phosphospecific antibody. Likewise, there was a substantial increase in the phosphorylation of the transcription factor CREB. Using the electrophoretic mobility shift assay (EMSA), we found a stimulation in the transcription factor NF-kappaB. The activations of CREB and NF-kappaB were blocked by inhibitors of either p38 (SB-203580) or MEK (PD-098059), suggesting that they were events downstream of MAK kinase. There was an increased secretion of BDNF and NGF into the conditioned medium, along with an increase in their messenger RNA. The inductions of BDNF and NGF were also blocked by inhibitors of p38 and MEK, as well as by the inhibition of NF-kappaB with a decoy DNA sequence. Taken together, the results suggest that GMF functions intracellularly in astrocytes as a modulator of MAP kinase signal transduction, leading to a series of downstream events including CREB and NF-kappaB activation, resulting in the induction and secretion of the neurotrophins.

Animals↗
PubMed2001

Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice.

Transcription factor activating transcription factor (ATF)-2 is activated by inflammatory signals transduced by the JNK and p38 MAP kinase pathways. To better define the role of ATF-2 in inflammation, adult mice expressing small amounts of a mutant ATF-2 protein were challenged with lipopolysaccharide (LPS), anti-CD3 antibody or virus. Within 3 h of challenge by LPS, ATF-2 mutant mice had decreased induction of the adhesion molecules E-selectin, P-selectin and VCAM-1 as well as the cytokines tumor necrosis factor-alpha, IL-1beta and IL-6 compared with control mice. Stimulation of T lymphocytes by anti-CD3 antibody also showed less induction of IL-1 and IL-6 in ATF-2 mutant tissues. ATF-2 mutant thymocytes treated with anti-CD3 antibody in vitro demonstrated reduced induction of c-Jun, JunB, JunD and Fra-2. However, similar to what was observed after p38 kinase inhibition in normal mice, relative ATF-2 deficiency did not prevent the development of a mononuclear cell infiltrate in the week following an inflammatory stimulus. ATF-2 mutant mice proved more susceptible to death than control mice from LPS plus D-galactosamine injection or Coxsackievirus B3 infection and had a higher incidence of mononuclear pulmonary infiltrates after exposure to Herpes simplex virus-1. ATF-2 is essential for maximal immediate induction of adhesion molecules and cytokine genes, but at later time points may even protect against overactive immune responses.

Activating Transcription Factor 2↗
PubMed2006

An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb ischemia.

OBJECTIVE: Angiogenesis is the growth and proliferation of blood vessels from existing vascular structures, and therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) is a prototypic angiogenic agent that exists in vivo in multiple isoforms, and studies with VEGF to date had used single isoform therapy with disappointing results. We tested plasmid and adenoviral vectors encoding a zinc-finger DNA-binding transcription factor (ZFP-32E) that was designed to increase the expression of all major VEGF isoforms in a preclinical model of peripheral arterial obstructive disease (PAOD) in hypercholesterolemic (ApoE knock-out) mice. METHODS: Unilateral femoral artery ligation/excision was performed in 117 mice. At 7 days postoperatively, the ischemic tibialis anterior (TA) and gastrocnemius (GAS) muscles received either ZFP-32E treatment (125 microg of plasmid, 2.5 x 10(11) viral particle units [vpu] of adenovirus; some mice received a second plasmid injection 3 days later) or no-ZFP treatment (125 microg of beta-galactosidase [beta-gal], a plasmid-lacking insert, or an equal dose of adenoviral encoding beta-gal; some mice received a second plasmid injection 3 days later). Group 1 mice (n = 31) were euthanized 3 days later, and VEGF messenger RNA (mRNA) and protein levels were measured. Group 2 mice (n = 38) were euthanized 7 days later, and measures of capillary density, cell proliferation, and apoptosis were quantified. Group 3 mice (n = 48) were euthanized 28 days later, and changes in lower limb blood flow perfusion were measured. RESULTS: In group 1, VEGF mRNA and protein levels were significantly higher in those with ZFP-32E treatment vs beta-gal. In group 2, capillary density and proliferating cells were significantly greater and apoptosis was significantly lower in those with ZFP-32E treatment vs beta-gal. Finally, in group 3, changes in the perfusion ratio (ischemic/nonischemic limb) at 21 days after injection were significantly greater in those with ZFP-32E treatment vs no-ZFP treatment. CONCLUSION: The ability of this engineered zinc-finger VEGF-activating transcription factor to induce therapeutic angiogenesis in hypercholesterolemic mice suggests this approach warrants investigation as a novel approach to treat PAOD.

Adenoviridae↗
PubMed1988

The JUN oncoprotein, a vertebrate transcription factor, activates transcription in yeast.

Transcriptional activation of RNA polymerase II in eukaryotic organisms ranging from yeasts to mammals has many common features such as enhancer elements, TATA elements, and activator proteins that bind specifically to promoter DNA. The JUN oncoprotein, which causes sarcomas in chickens, shows significant homology to the DNA-binding domain of GCN4, a yeast protein that stimulates transcription of the amino acid biosynthetic genes. The GCN4 and JUN proteins bind the same DNA sequences, consensus ATGA(C/G)TCAT, even though the DNA-binding domains are only 45% identical in amino acid sequence. The JUN protein almost certainly represents the oncogenic version of the normal AP-1 transcription factor, suggesting an evolutionary relationship between yeast and vertebrate activator proteins. Here, I demonstrate that JUN efficiently activates transcription in yeast either through its own or a heterologous DNA-binding domain. As is the case for yeast activator proteins, transcriptional stimulation by JUN requires an acidic activation region distinct from the DNA-binding domain. The functional interchangeability between yeast and vertebrate transcription factors strongly suggests a basic similarity in the molecular mechanism of eukaryotic transcriptional activation.

Amino Acid Sequence↗
PubMed1998

Glucose rapidly and reversibly decreases INS-1 cell insulin gene transcription via decrements in STF-1 and C1 activator transcription factor activity.

We have reported that chronic exposure of HIT-T15 cells to supraphysiological concentrations of glucose over many months leads to decreased insulin gene transcription and decreased binding activities of two beta-cell-specific transcription factors, STF-1 and C1 activators, and have postulated that these events may provide a mechanism for glucose toxicity on beta-cell function. We now report that culturing the highly differentiated rat insulinoma cell line, INS-1, in glucose concentrations above 8.0 mM caused a marked decrease in insulin mRNA levels within 24 h. The decrease in insulin mRNA levels was reversed by further incubation of the cells in 4.0 mM glucose. Transient transfection of a chloramphenicol acetyltransferase reporter gene regulated by the 5'-regulatory sequences of the human insulin gene showed that elevated glucose concentrations caused a large decrease in insulin gene promoter activity. The decrease in insulin gene promoter activity was associated with reductions in the binding activities of both STF-1 and C1 activator, and these were partially reversed by lowering the glucose concentration. The decrease in STF-1 binding activity was associated with decreased STF-1 mRNA and occurred independently of changes in STF-1 promoter activity, suggesting a posttranscriptional regulatory mechanism. Furthermore, the decrease in insulin gene expression was found to occur independently of changes in cell proliferation. We conclude that physiologically relevent elevations in glucose can reversibly diminish insulin gene transcription by reducing the expression and/or binding activity of two critical beta-cell transcription factors.

Animals↗
PubMed1991

Heat shock transcription factor activates transcription of the yeast metallothionein gene.

In the yeast Saccharomyces cerevisiae, transcription of the metallothionein gene CUP1 is induced by copper and silver. Strains with a complete deletion of the ACE1 gene, the copper-dependent activator of CUP1 transcription, are hypersensitive to copper. These strains have a low but significant basal level of CUP1 transcription. To identify genes which mediate basal transcription of CUP1 or which activate CUP1 in response to other stimuli, we isolated an extragenic suppressor of an ace1 deletion. We demonstrate that a single amino acid substitution in the heat shock transcription factor (HSF) DNA-binding domain dramatically enhances CUP1 transcription while reducing transcription of the SSA3 gene, a member of the yeast hsp70 gene family. These results indicate that yeast metallothionein transcription is under HSF control and that metallothionein biosynthesis is important in response to heat shock stress. Furthermore, our results suggest that HSF may modulate the magnitude of individual heat shock gene transcription by subtle differences in its interaction with heat shock elements and that a single-amino-acid change can dramatically alter the activity of the factor for different target genes.

Amino Acid Sequence↗
PubMed2000

Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression.

Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.

Activating Transcription Factor 2↗
PubMed1997

Expression of activating transcription factor-2, serum response factor and cAMP/Ca response element binding protein in the adult rat brain following generalized seizures, nerve fibre lesion and ultraviolet irradiation.

The expression of the constitutive transcription factors activating transcription factor-2 (ATF-2), serum response factor (SRF) and cAMP/Ca response element binding factor (CREB), and the phosphorylation of SRF and CREB were studied in the untreated adult rat nervous system and following seizure activities and neurodegenerative stimuli. In the untreated rat, intense nuclear SRF immunoreactivity was present in the vast majority of neurons in the forebrain, cortex, striatum, amygdala and hippocampus, and in some scattered neurons in the medulla and spinal cord. In contrast, SRF immunoreactivity was absent in the midline areas of the forebrain, e.g., the globus pallidum and septum, and in the hypothalamus, thalamus, mesencephalon and motoneurons. Nuclear ATF-2 was expressed at high levels in apparently all neurons, but not glial cells, throughout the neuraxis except for those neuronal populations which exhibit a high basal level of c-Jun, i.e. dentate gyrus and the motoneurons of cranial and somatosensory neurons. CREB immunoreactivity was present at a rather uniform intensity in all neuronal and glial cells throughout the neuraxis. Two hours, but not 5 h or 24 h, following systemic application of kainic acid, an increase in SRF was detectable by western blot analysis in hippocampal and cortical homogenates whereas the expression of ATF-2 and CREB did not change. Phosphorylation of CREB at serine 133 and of SRF at serine 103 were studied with specific antisera. In untreated rats, intense phosphoCREB and phosphoSRF immunoreactivities labelled many glial cells and/or neurons with the highest levels in the dentate gyrus, the entorhinal cortex and the retrosplenial cortex. Following kainate-induced seizures, phosphoSRF-IR but not phosphoCREB-IR transiently increased between 0.5 h and 2 h. Following transection of peripheral or central nerve fibres such as optic nerve, medial forebrain bundle, vagal and facial nerve fibres, ATF-2 rapidly decreased in the axotomized neurons during that period when c-Jun was rapidly expressed. SRF remained unchanged and CREB disappeared in some axotomized subpopulations. Similar to axotomy, c-Jun increased and ATF-2 decreased in cultured adult dorsal root ganglion neurons following ultraviolet irradiation. The distribution of SRF and ATF-2 suggests that their putative target genes c-fos, junB, krox-24 and c-jun can be independently regulated from SRF and ATF-2. The suppression of ATF-2 and the expression of c-Jun following axotomy and ultraviolet irradiation might be part of a novel neuronal stress response in the brain that strongly resembles the stress response characterized in non-neuronal cells.

Activating Transcription Factor 2↗
PubMed1999

Identification of the cyclin D1 gene as a target of activating transcription factor 2 in chondrocytes.

Endochondral bone growth is regulated by the rates of chondrocyte proliferation and differentiation. However, the intracellular mechanisms regulating these processes are poorly understood. Recently, interruption of the gene encoding the transcription factor activating transcription factor 2 (ATF-2) was shown to inhibit proliferation of chondrocytes in mice [Reimold, A. M., et al. (1996) Nature (London) 379, 262-265]. The target genes of ATF-2 that are responsible for this phenotype remain unknown. Here we report that the cyclin D1 gene is a direct target of ATF-2 in chondrocytes. ATF-2 is present in nuclear extracts from chondrogenic cell lines and binds, as a complex with a CRE-binding protein (CREB)/CRE modulator protein, to the cAMP response element (CRE) in the cyclin D1 promoter. Mutation of the cyclin D1 CRE caused a 78% reduction in the activity of the promoter in chondrocytes. Overexpression of ATF-2 in chondrocytes enhanced activity of the cyclin D1 promoter 3. 5-fold. In contrast, inhibition of endogenous ATF-2 or CREB by expression of dominant-negative inhibitors of CREB and ATF-2 significantly reduced the activity of the promoter in chondrocytes through the CRE. In addition, levels of cyclin D1 protein are greatly reduced in the chondrocytes of ATF-2-deficient mice. These data identify the cyclin D1 gene as a direct target of ATF-2 in chondrocytes and suggest that reduced expression of cyclin D1 contributes to the defective cartilage development of these mice.

Activating Transcription Factor 2↗
PubMed2003

Subcellular localization of activating transcription factor 2 in melanoma specimens predicts patient survival.

The transcription factor activating transcription factor 2 (ATF2) has been shown to be associated with melanocytic oncogenesis and melanoma tumor proliferation in preclinical models. The clinical significance of ATF2 expression is unknown. To determine the prognostic value of ATF2 in melanoma, we evaluated the pattern and level of ATF2 expression in a large cohort of melanoma specimens. Immunohistochemical staining was performed on a tissue microarray representing 544 patients with a mean follow-up time of 60 months. Expression was evaluated semiquantitatively and correlated with overall survival and other clinicopathological data. Strong cytoplasmic ATF2 expression was associated with primary specimens rather than metastases (P < 0.0001) and with better survival (P = 0.0003). Strong nuclear ATF2 expression was associated with metastatic specimens (P < 0.0001) and with poor survival (P = 0.0008). Patients who had both weak cytoplasmic and strong nuclear ATF2 staining had the worst outcome, both among the full cohort of patients (P < 0.0001) and among the patients with localized disease (n = 269; P < 0.0001). On multivariate analysis of the primary cutaneous specimens, weak cytoplasmic staining and strong nuclear staining was an independent predictor of poor outcome, as was Clark level. Nuclear ATF2 is likely to be transcriptionally active, whereas cytoplasmic ATF2 probably represents an inactive form. These findings support other preclinical findings in which transcriptionally active ATF2 is involved in tumor progression-proliferation in melanoma. Moreover, our findings suggest that ATF2 might be a useful prognostic marker in early-stage melanoma.

Activating Transcription Factor 2↗
PubMed2005

Downregulation of activating transcription factor 5 is required for differentiation of neural progenitor cells into astrocytes.

The mechanisms that regulate neural progenitor cell differentiation are primarily unknown. The transcription factor activating transcription factor 5 (ATF5) is expressed in neural progenitors of developing brain but is absent from mature astrocytes and neurons. Here, we demonstrate that ATF5 regulates the conversion of ventricular zone (VZ) and subventricular zone (SVZ) neural progenitors into astrocytes. Constitutive ATF5 expression maintains neural progenitor cell proliferation and blocks their in vitro and in vivo differentiation into astrocytes. Conversely, loss of ATF5 function promotes cell-cycle exit and allows astrocytic differentiation in vitro and in vivo. CNTF, a promoter of astrocytic differentiation, downregulates endogenous ATF5, whereas constitutively expressed ATF5 suppresses CNTF-promoted astrocyte genesis. Unexpectedly, constitutive ATF5 expression in neonatal SVZ cells both in vitro and in vivo causes them to acquire properties and anatomic distributions of VZ cells. These findings identify ATF5 as a key regulator of astrocyte formation and potentially of the VZ to SVZ transition.

Activating Transcription Factors↗