The Activating Transcription Factor 3 Protein Suppresses the Oncogenic Function of Mutant p53 Proteins

Abstract

Background: Mutant p53 often acquires tumor-promoting activities, including the promotion of cancer cell survival, invasion, and metastasis. Results: Activating transcription factor 3 (ATF3) bound mutant p53 proteins, sensitized cancer cells to chemotherapy, and suppressed mutant p53-mediated cell migration. Conclusion: ATF3 suppressed the tumor-promoting function of mutant p53. Significance: Targeting ATF3 could be a novel strategy for treating p53-mutated cancer.

The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins

“…cisplatin) often induce ATF3 expression and cause DNA damage, our findings also suggest that ATF3 might mediate different cellular responses resulting in either sensitization of, or resistance to, therapies in cancer cells with different p53 mutation status. Indeed, although ATF3 is often regarded as a proapoptotic molecule (22), it was also shown to suppress apoptosis induced by cisplatin in T98G glioblastoma cells (37). Although the p53 status in T98G cells remains controversial, our results support targeting ATF3 as an effective strategy for treating p53-mutated cancers (22).…”

“…Indeed, although ATF3 is often regarded as a proapoptotic molecule (22), it was also shown to suppress apoptosis induced by cisplatin in T98G glioblastoma cells (37). Although the p53 status in T98G cells remains controversial, our results support targeting ATF3 as an effective strategy for treating p53-mutated cancers (22).…”

Activating transcription factor 3 is downregulated in hepatocellular carcinoma and functions as a tumor suppressor by regulating cyclin D1

“…Although it was previously shown to be a metastasis promoter in a murine B16 melanoma model, other groups have found that ATF3 could suppress invasion and metastasis of lung and bladder cancers [12,13]. Similarly, ATF3 may be oncogenic as it can be protective against apoptosis, but it was found to be induced following DNA damage in colon cancer cells and suppressed the growth of HeLa cells [14,15].…”

Inhibition of ERN1 signaling enzyme affects hypoxic regulation

“…At the same time, ATF3 can suppress mutant TP53 oncogenic function, thereby contributing to tumor suppression in TP53-mutated cancer as well as promotes colon cancer metastasis and involved in the progress of laryngeal squamous cell carcinoma [37][38][39]. It was also found that ATF3 is strongly induced during necrosis but not apoptosis and knockdown of ATF3 by siRNA in the F28-7 cells resulted in apoptotic morphology rather than necrotic morphology [40].…”

“…Thus, transcription factor HOXC6 may contribute to suppression of proliferation rate of glioma cells without ERN1 signaling enzyme function. Moreover, the decreased expression level of aTf3 and ePaS1 genes in ERN1 knockdown glioma cells may also contribute to suppression of proliferation, because these transcription factors play an important role in the control of tumor growth [25,26,[37][38][39]42]. At the same time, blockade of ERN1 signaling enzyme function enhances the hypoxic regulation of aTf3 and ePaS1 gene expressions, but prospective studies are still needed to clarify the significance of these results.…”