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 theirin vitroandin vivodifferentiation into astrocytes. Conversely, loss of ATF5 function promotes cell-cycle exit and allows astrocytic differentiationin vitroandin 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 bothin vitroandin vivocauses 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.

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

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. Mol Cancer Res; 8(8); 1105–15. ©2010 AACR.

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.