ATF5 Gene Editing

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ATF5 Gene Editing    

Activating transcription factor 5 (ATF5), which is also called ATFx, is a member of the ATF/cAMP response element-binding (CREB) protein family of basic leucine zipper proteins. ATF5 is expressed in many types of adult tissues, with particularly high expression in the liver. Like other family members, ATF5 possesses a basic DNA-binding domain, an N-terminal sequence for transactivation, a leucine zipper comprising several leucine-rich heptad repeats, and a C-terminal domain. ATF5 is involved in cell survival, proliferation, and inhibition of neural differentiation. Besides, several studies have suggested that ATF5 plays a crucial role in promoting cell survival in various cell types, including cervical cancer, glioblastoma, breast cancer, lymphocytes, and cardiomyocytes.

Biological Functions of ATF5

Many studies have reported that ATF5 plays an important role in modulating differentiation pathways in multiple tissues such as the bone, liver, brain, and fat. Among them, ATF5-mediated differentiation of neural tissues was most well characterized. ATF5 upregulates both the Cycd3 and Egr1 genes that are involved in proliferation. EGR1 also plays a role in cellular survival pathways in conjunction with the ATF5 transcriptionally regulated anti-apoptotic genes MCL1 and BCL2. Deubiquitinase USP9X expression is also governed by ATF5, and USP9X post-translationally stabilizes MCL1, BCL2, and the MCL1-stability protein, BAG3. ATF5 itself is stable through binding to heat shock protein 70 (HSP70), but is degraded by binding to nucleophosmin in hepatocellular carcinomas. In stress conditions, ATF5 is transcriptionally induced by amino acid starvation or cytotoxicity, and is translationally induced by endoplasmic reticulum stress, heat shock, or arsenite exposure. The latter promotes phosphorylation of eukaryotic initiation factor eIF2, resulting in the translation of ATF5 from the first translation initiation site. ATF5-mediated rescue of cells from stress is achieved by the upregulation of chaperone HSPs. Given these roles, it is clear that ATF5 may promote cancer cell proliferation and protect these cells from stress.

ATF5 and Cancer

ATF5 is widely detected in immunohistochemical staining of carcinoma tissue microarrays, and nuclear localization of ATF5 is higher in neoplastic tissues than in non-tumour tissues. In fact, by analyzing the expression levels of ATF5 in a variety of cancer types, it is evident that ATF5 expression is highly upregulated in various types of cancer such as breast cancer, lung cancer, glioma, and numerous others. This shows an oncogenic role for ATF5 in these cancer types where overexpression is seen in malignant tissues. The expression of ATF5 is also significantly associated with tumor grade in several cancer types. In addition to these functions is the novel role for ATF5 as a structural protein where it facilitates the formation of the centrosome, thus suggesting ATF5 may promote proper mitotic function. Another interesting property for ATF5 in cancer is seen in hepatocellular carcinoma where ATF5 seems to possess a tumor suppressor role.

Development of ATF5 Peptide Drugs

ATF5 possesses many properties that make it an attractive target for cancer treatment. The role of ATF5 in the transcriptional activation of proteins such as BCL2, mTOR, and MCL1 suggests the importance of ATF5 in modulating activity of pathways critical to the development of cancer. The ATF5 antagonist (dominant negative ATF5; d/n-ATF5) was designed as a N-terminally truncated construct, in which the DNA-binding domain is replaced by an acidic amphipathic a-helical sequence predominantly containing heptad leucine repeats, while the leucine zipper and C-terminal domains of ATF5 remained unchanged. Transfection of a d/n-ATF5 transgene was found to trigger massive apoptosis in breast, ovarian, glioma, and pancreatic cancer cell lines. Infection of rat brain glioma allografts with a d/n-ATF5 retrovirus led to massive apoptosis of tumor cells, but not of normal astrocytes. Induction of transgenic d/n-ATF5 in a mouse model in which gliomas were generated from resident neural progenitors led to tumor prevention or complete eradication.

Proposed mechanisms for dnATF5 anticancer activity. Figure 1. Proposed mechanisms for dnATF5 anticancer activity. (Sears T K, Angelastro J M., 2017)

Efforts are being made to identify transcription factors that directly bind to ATF5 and serve as partners in the regulation of prosurvival genes. The identification of drug candidates that block the function of downstream prosurvival proteins would open up the way for multi-target therapy of ATF5 and its binding partners, so as to prolong and improve the efficacy of disruption of prosurvival gene function and maximize the efficacy of anticancer therapy.

ATF5 Gene Editing Service

CRISPR/Cas9 PlatformCB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively ATF5 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

  • ATF5 Gene Knockout: We offer ATF5 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service that covers from sgRNA design and construct, pronuclear microinjection to Founders genotyping and breeding.
  • ATF5 Gene Knockin: CRISPR/Cas9 PlatformCB provides the one-stop ATF5 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of ATF5 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

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References

  1. Nukuda A, et al. Role of ATF5 in the invasive potential of diverse human cancer cell lines. Biochemical and biophysical research communications, 2016, 474(3): 509-514.
  2. Angelastro J M. Targeting ATF5 in cancer. Trends in cancer, 2017, 3(7): 471-474.
  3. Sears T K, Angelastro J M. The transcription factor ATF5: role in cellular differentiation, stress responses, and cancer. Oncotarget, 2017, 8(48): 84595.
For research use only. Not intended for any clinical use.

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