Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.

The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.

Activating Transcription Factor 5 Promotes Neuroblastoma Metastasis by Inducing Anoikis Resistance.

MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion-induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. SIGNIFICANCE: This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma.

A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant properties.

Targeting common oncogenic drivers of glioblastoma multiforme (GBM) in patients has remained largely ineffective, raising the possibility that alternative pathways may contribute to tumor aggressiveness. Here we demonstrate that Vangl1 and Fzd7, components of the non-canonical Wnt planar cell polarity (Wnt/PCP) signaling pathway, promote GBM malignancy by driving cellular proliferation, migration, and invasiveness, and engage Rho GTPases to promote cytoskeletal rearrangements and actin dynamics in migrating GBM cells. Mechanistically, we uncover the existence of a novel Vangl1/Fzd7 complex at the leading edge of migrating GBM cells and propose that this complex is critical for the recruitment of downstream effectors to promote tumor progression. Moreover, we observe that depletion of FZD7 results in a striking suppression of tumor growth and latency and extends overall survival in an intracranial mouse xenograft model. Our observations support a novel mechanism by which Wnt/PCP components Vangl1 and Fzd7 form a complex at the leading edge of migratory GBM cells to engage downstream effectors that promote actin cytoskeletal rearrangements dynamics. Our findings suggest that interference with Wnt/PCP pathway function may offer a novel therapeutic strategy for patients diagnosed with GBM.

Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers.

Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies.

Cell-Penetrating CEBPB and CEBPD Leucine Zipper Decoys as Broadly Acting Anti-Cancer Agents.

Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine-zipper-based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides similarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non-transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubicin), the peptides acted additively to synergistically and were fully active on Taxol-resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6, IL8 and asparagine synthetase (ASNS), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro-survival survivin and a required elevation of pro-apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a variety of cancers as mono- or combination therapies.

Repurposing FDA approved drugs inhibiting mitochondrial function for targeting glioma-stem like cells.

Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 µM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.

Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells.

Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM.

PRMT1 promotes neuroblastoma cell survival through ATF5.

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.

Cetylpyridinium chloride is a potent AMP-activated kinase (AMPK) inducer and has therapeutic potential in cancer.

AMP-activated protein kinase (AMPK) is a eukaryotic energy sensor and protector from mitochondrial/energetic stress that is also a therapeutic target for cancer and metabolic disease. Metformin is an AMPK inducer that has been used in cancer therapeutic trials. Through screening we isolated cetylpyridinium chloride (CPC), a drug known to dose-dependently inhibit mitochondrial complex 1, as a potent and dose-dependent AMPK stimulator. Mitochondrial biogenesis and bioenergetics changes have also been implicated in glioblastoma, which is the most aggressive form of brain tumors. Cetylpyridinium chloride has been administered in humans as a safe drug-disinfectant for several decades, and we report here that under in vitro conditions, cetylpyridinium chloride kills glioblastoma cells in a dose dependent manner at a higher efficacy compared to current standard of care drug, temozolomide.

Dominant-Negative ATF5 Compromises Cancer Cell Survival by Targeting CEBPB and CEBPD.

The basic leucine zipper transcription factor ATF5 is overexpressed in many tumor types and interference with its expression or function inhibits cancer cell survival. As a potential therapeutic approach to exploit these findings, we created dominant-negative (DN) ATF5 forms lacking DNA-binding ability that retain the ATF5 leucine zipper, and thus associate with and sequester ATF5's requisite leucine zipper-binding partners. Preclinical studies with DN-ATF5, including a cell-penetrating form, show in vitro and in vivo efficacy in compromising cancer cell survival. However, DN-ATF5's targets, and particularly those required for tumor cell survival, have been unknown. We report that cells lacking ATF5 succumb to DN-ATF5, indicating that ATF5 itself is not DN-ATF5's obligate target. Unbiased pull-down assays coupled with mass spectrometry and immunoblotting revealed that DN-ATF5 associates in cells with the basic leucine zipper proteins CEBPB and CEBPD and coiled-coil protein CCDC6. Consistent with DN-ATF5 affecting tumor cell survival by suppressing CEBPB and CEBPD function, DN-ATF5 interferes with CEBPB and CEBPD transcriptional activity, while CEBPB or CEBPD knockdown promotes apoptotic death of multiple cancer cells lines, but not of normal astrocytes. We propose a two-pronged mechanism by which DN-ATF5 kills tumor cells. One is by inhibiting heterodimer formation between ATF5 and CEBPB and CDBPD, thus suppressing ATF5-dependent transcription. The other is by blocking the formation of transcriptionally active CEBPB and CEBPD homodimers as well as heterodimers with partners in addition to ATF5. IMPLICATIONS: This study indicates that the potential cancer therapeutic DN-ATF5 acts by associating with and blocking the transcriptional activities of CEBPB and CEBPD.

Dominant-negative ATF5 rapidly depletes survivin in tumor cells.

Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

The transcription factor ATF5: role in cellular differentiation, stress responses, and cancer.

Activating transcription factor 5 (ATF5) is a cellular prosurvival transcription factor within the basic leucine zipper (bZip) family that is involved in cellular differentiation and promotes cellular adaptation to stress. Recent studies have characterized the oncogenic role of ATF5 in the development of several different types of cancer, notably glioblastoma. Preclinical assessment of a systemically deliverable dominant-negative ATF5 (dnATF5) biologic has found that targeting ATF5 results in tumor regression and tumor growth inhibition of glioblastoma xenografts in mouse models. In this review, we comprehensively and critically detail the current scientific literature on ATF5 in the context of cellular differentiation, survival, and response to stressors in normal tissues. Furthermore, we will discuss how the prosurvival role of ATF5 aides in cancer development, followed by current advances in targeting ATF5 using dominant-negative biologics, and perspectives on future research.

Targeting ATF5 in Cancer.

The expression of activating transcription factor 5 (ATF5) correlates negatively with patient survival in different types of cancer. ATF5 is important for the survival and proliferation of cancer cells, and can be targeted to selectively trigger cancer cell apoptosis while sparing normal cells. Cell-penetrating peptides combined with a dominant negative ATF5 cargo have recently shown efficacy against brain, breast, melanoma, and prostate cancers.

A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers.

PURPOSE: Despite significant progress in cancer research, many tumor entities still have an unfavorable prognosis. Activating transcription factor 5 (ATF5) is upregulated in various malignancies and promotes apoptotic resistance. We evaluated the efficacy and mechanisms of the first described synthetic cell-penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1. EXPERIMENTAL DESIGN: Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models. RESULTS: CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment-refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and led to diminished levels of antiapoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in glioblastoma, melanoma, prostate cancer, and triple receptor-negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own. CONCLUSIONS: Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe, and efficient antineoplastic agent against treatment-resistant cancers. Clin Cancer Res; 22(18); 4698-711. ©2016 AACR.

Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide.

Malignant gliomas have poor prognosis and urgently require new therapies. Activating Transcription Factor 5 (ATF5) is highly expressed in gliomas, and interference with its expression/function precipitates targeted glioma cell apoptosis in vitro and in vivo. We designed a novel deliverable truncated-dominant-negative (d/n) form of ATF5 fused to a cell-penetrating domain (Pen-d/n-ATF5-RP) that can be intraperitoneally/subcutaneously administered to mice harboring malignant gliomas generated; (1) by PDGF-B/sh-p53 retroviral transformation of endogenous neural progenitor cells; and (2) by human U87-MG xenografts. In vitro Pen-d/n-ATF5-RP entered into glioma cells and triggered massive apoptosis. In vivo, subcutaneously-administered Pen-d/n-ATF5-RP passed the blood brain barrier, entered normal brain and tumor cells, and then caused rapid selective tumor cell death. MRI verified elimination of retrovirus-induced gliomas within 8-21 days. Histopathology revealed growth-suppression of intracerebral human U87-MG cells xenografts. For endogenous PDGF-B gliomas, there was no recurrence or mortality at 6-12 months versus 66% mortality in controls at 6 months. Necropsy and liver-kidney blood enzyme analysis revealed no adverse effects on brain or other tissues. Our findings thus identify Pen-d/n-ATF5-RP as a potential therapy for malignant gliomas.

Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells.

Precise regulation of neuroprogenitor cell proliferation and differentiation is required for successful brain development, but the factors that contribute to this are only incompletely understood. The transcription factor ATF5 promotes proliferation of cerebral cortical neuroprogenitor cells and its down regulation permits their differentiation. Here, we examine the expression and regulation of ATF5 in cerebellar granule neuron progenitor cells (CGNPs) as well as the role of ATF5 in the transition of CGNPs to postmitotic cerebellar granule neurons (GCNs). We find that ATF5 is expressed by proliferating CGNPs in both the embryonic and postnatal cerebellar external granule layer (EGL) and in the rhombic lip, the embryonic structure from which the EGL arises. In contrast, ATF5 is undetectable in postmitotic GCNs. In highly enriched dissociated cultures of CGNPs and CGNs, ATF5 is expressed only in CGNPs. Constitutive ATF5 expression in CGNPs does not affect their proliferation or exit from the cell cycle. In contrast, in presence of sonic hedgehog (Shh), a mitogen for CGNPs, constitutively expressed ATF5 promotes CGNP proliferation and delays their cell cycle exit and differentiation. Conversely, ATF5 loss-of-function conferred by a dominant-negative form of ATF5 significantly diminishes Shh-stimulated CGNP proliferation and promotes differentiation. In parallel with its stimulation of CGNP proliferation, Shh enhances ATF5 expression by what appeared to be a posttranscriptional mechanism involving protein stabilization. These findings indicate a reciprocal interaction between ATF5 and Shh in which Shh stimulates ATF5 expression and in which ATF5 contributes to Shh-stimulated CGNP expansion.

Premutation CGG-repeat expansion of the Fmr1 gene impairs mouse neocortical development.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder caused by a premutation CGG-trinucleotide repeat expansion (55-200 CGG repeats) within the 5'-untranslated region of the FMR1 gene. Although FXTAS generally affects premutation carriers over 50 years of age, cognitive and psychological symptoms can appear in carriers during childhood, suggesting that the FMR1 premutation affects brain function early in life. Recent work with cultured hippocampal neurons from a premutation (Fmr1 CGG knock-in) mouse model revealed impaired development of early postnatal neurons, consistent with the developmental clinical involvement of premutation carriers. In the current work, we show that the presence of premutation CGG-repeat expansions in the mouse Fmr1 gene alters embryonic neocortical development. Specifically, embryonic premutation mice display migration defects in the neocortex and altered expression of neuronal lineage markers. The current data demonstrate that premutation alleles of the Fmr1 gene are associated with defects in developmental programs operating during prenatal stages of brain formation and provide further evidence that the FMR1 premutation has a neurodevelopmental component.

Overexpression of CD133 promotes drug resistance in C6 glioma cells.

Glioblastoma multiforme is an extremely aggressive and clinically unresponsive form of cancer. Transformed neoplastic neural stem cells, resistant to chemotherapy and radiation therapy, are thought to be responsible for the initial tumor formation and the recurrence of disease following surgical resection. These stem cells express multidrug resistance markers along with CD133. We show that ectopic overexpression of CD133 in rat C6 glioma cells leads to significant reluctance to undergo apoptosis from camptothecin and doxorubicin. Although p53 was upregulated in CD133-overexpressing glioma cells treated with DNA-damaging agents, apoptosis seems to be p53 independent. At least one ABC transporter, rat P-glycoprotein/ABCB1, was upregulated by 62% in CD133(+) cells with a corresponding increase in activity. Thus, the combination of higher P-glycoprotein mRNA transcription and elevated transporter activity seems to contribute to the protection from cytotoxic reagents. In conclusion, previous investigators have reported that resilient cancer stem cells coexpress CD133 and ABC transporters with increased reluctance toward apoptosis. Our data suggest that CD133 may contribute to the observed resistance to apoptosis of CD133(+) cancer stem cells.

Identification of a novel DNA binding site and a transcriptional target for activating transcription factor 5 in c6 glioma and mcf-7 breast cancer cells.

Recent reports indicate that the activating transcription factor 5 (ATF5) is required for the survival of cancer cells but not for noncancer cells. However, the mechanisms by which ATF5 regulates genes and promotes cell survival are not clear. Using a cyclic amplification and selection of targets (CASTing) approach, we identified a novel ATF5 consensus DNA binding sequence. We show in C6 glioma and MCF-7 breast cancer cells that ATF5 occupies this sequence and that ATF5 activates reporter gene expression driven by this site. Conversely, reporter activity is diminished when ATF5 activity is blocked or when ATF5 expression is down-regulated by serum withdrawal. We further show that early growth response factor 1 (Egr-1), whose promoter contains two adjacent ATF5 consensus binding sites at a conserved promoter position in rat, mouse, and human, is targeted and regulated by ATF5 in C6 and MCF-7 cells. These data provide new insight on the mechanisms by which ATF5 promotes gene regulation and cancer-specific cell survival.

The transcription factor ATF5: role in neurodevelopment and neural tumors.

We review recent findings regarding the properties of ATF5 and the major roles that this transcription factor plays in development of the nervous system and in survival of neural tumors. ATF5 is a widely expressed basic leucine zipper protein that has been subject to limited characterization. It is highly expressed in zones of neuroprogenitor cell proliferation. In vitro and in vivo studies indicate that it functions there to promote neuroprogenitor cell expansion and to suppress their differentiation into neurons or glia. ATF5 expression is down-regulated by trophic factors and this is required for their capacity to promote neuroprogenitor cell cycle exit and differentiation into either neurons, oligodendroglia or astrocytes. ATF5 is also highly expressed in a number of tumor types, including neural tumors such as neuroblastomas, medulloblastomas and glioblastomas. Examination of the role of ATF5 in glioblastoma cells indicates that interference with its expression or activity causes them to undergo apoptotic death. In contrast, normal astrocytes and neurons do not appear to require ATF5 for survival, indicating that it may be a selective target for treatment of glioblastomas and other neural neoplasias. Further studies are needed to identify the transcriptional targets of ATF5 and the mechanisms by which its expression is regulated in neuroprogenitors and tumors.