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Dominant-negative ATF5 rapidly depletes survivin in tumor cells. 2019

Xiaotian Sun, and James M Angelastro, and David Merino, and Qing Zhou, and Markus D Siegelin, and Lloyd A Greene
Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.

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.

UI MeSH Term Description Entries
D005822 Genetic Vectors DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition. Cloning Vectors,Shuttle Vectors,Vectors, Genetic,Cloning Vector,Genetic Vector,Shuttle Vector,Vector, Cloning,Vector, Genetic,Vector, Shuttle,Vectors, Cloning,Vectors, Shuttle
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000076722 Drug Development The entire process of bringing a new drug to the market. It includes both preclinical and clinical testing, and regulatory approval. Computational Prediction of Drug-Target Interactions,Drug Target Prediction,Medication Development,Pharmaceutical Development,Development, Drug,Development, Medication,Development, Pharmaceutical,Drug Target Predictions,Prediction, Drug Target,Target Prediction, Drug
D000077022 Survivin An apoptosis inhibitory protein that contains a single baculoviral IAP repeat (BIR) domain. It associates with MICROTUBULES and functions to regulate cell proliferation as a component of the chromosome passage protein complex (CPC), performing essential roles for localization of the complex, chromosome alignment, segregation during MITOSIS and CYTOKINESIS, and assembly of the MITOTIC SPINDLE. It is expressed by fetal kidney and liver cells and highly expressed in ADENOCARCINOMA and high-grade LYMPHOMA. BIRC5 Protein,Baculoviral IAP Repeat-containing Protein 5,Baculoviral IAP Repeat containing Protein 5
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014162 Transfection The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES. Transfections
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D043222 Ubiquitin Thiolesterase A thioester hydrolase which acts on esters formed between thiols such as DITHIOTHREITOL or GLUTATHIONE and the C-terminal glycine residue of UBIQUITIN. Neuron Cytoplasmic Protein 9.5,PARK5 Protein,Parkinson Disease 5 Protein,UCHL1 Protein,Ubiquitin C-Terminal Esterase,Ubiquitin C-Terminal Hydrolase,Ubiquitin Carboxy-Terminal Esterase,Ubiquitin Carboxy-Terminal Hydrolase,Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1,Uch-L1 Protein,C-Terminal Esterase, Ubiquitin,C-Terminal Hydrolase, Ubiquitin,Carboxy-Terminal Esterase, Ubiquitin,Carboxy-Terminal Hydrolase, Ubiquitin,Esterase, Ubiquitin C-Terminal,Esterase, Ubiquitin Carboxy-Terminal,Hydrolase, Ubiquitin C-Terminal,Hydrolase, Ubiquitin Carboxy-Terminal,Thiolesterase, Ubiquitin,Ubiquitin C Terminal Esterase,Ubiquitin C Terminal Hydrolase,Ubiquitin Carboxy Terminal Esterase,Ubiquitin Carboxy Terminal Hydrolase,Ubiquitin Carboxyl Terminal Hydrolase Isozyme L1,Uch L1 Protein
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

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