The Ras-ERK Signaling Pathway Regulates Acetylated Activating Transcription Factor 2 Via P300 in Pancreatic Cancer Cells

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2020 Nov 12

PMID 33178766

Citations 2

Authors

Mu Li

Shao-Wei Song

Yang Ge

Jun-Yi Jin

Xiao-Ying Li

Xiao-Dong Tan

Affiliations

Soon will be listed here.

Abstract

Background: Activating transcription factor 2 (ATF2) regulates the expression of downstream target genes and is phosphorylated by the Ras-extracellular-signal-regulated kinase (ERK) pathway. Acetylation of ATF2 is necessary for this type of regulation. However, the molecular mechanism by which the Ras-ERK pathway mediates the regulation of acetylated ATF2 is unknown. This study investigates the mechanism of Ras-ERK pathway-mediated regulation of acetylated ATF2 in maintaining the characteristic phenotype of pancreatic cancer cells.

Methods: This study was carried out using ASPC-1 and BXPC-3 pancreatic cancer cell lines transfected with the double mutant Ras. The levels of phosphorylated ERK1/2 were measured to establish the activated Ras-ERK pathway. The regulation of acetylated ATF2 was examined by detecting the protein level using western blotting, and the effects on cancer cell phenotype were measured using cell viability, proliferation, migration, and apoptosis assays. Also, chromatin immunoprecipitation (ChIP) assays were used to measure the effect on respective downstream target genes.

Results: The results showed that Ras reduced the level of acetylated ATF2 in ASPC-1 and BXPC-3 cells. Compared to wild-type ATF2, the mutant ATF2 (which mimics the irreversible acetylated form of ATF2) reduced the cancer cell phenotype and showed decreased enrichment on target genes upon transfection with Ras. Moreover, the level of acetylated ATF2 was regulated by the degradation of p300 through E3 ubiquitin ligase mouse double minute 2 homolog (MDM2).

Conclusions: Activation of the Ras-ERK pathway regulates acetylated ATF2 through degradation of p300 via a proteasome-dependent pathway, which alters the transcription of downstream target genes responsible for the cancer cell phenotype.

Citing Articles

The Activation of p300 Enhances the Sensitivity of Pituitary Adenomas to Dopamine Agonist Treatment by Regulating the Transcription of DRD2.

Li S, Li X, Wang Q, Jiang Q, Wang Z, Xu L Int J Mol Sci. 2024; 25(23).

PMID: 39684198 PMC: 11641041. DOI: 10.3390/ijms252312483.

Effects of the Acetyltransferase p300 on Tumour Regulation from the Novel Perspective of Posttranslational Protein Modification.

Zeng Q, Wang K, Zhao Y, Ma Q, Chen Z, Huang W Biomolecules. 2023; 13(3).

PMID: 36979352 PMC: 10046601. DOI: 10.3390/biom13030417.

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