The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress

Abstract

Activating transcription factor 4 (ATF4) is well known for its role in the endoplasmic reticulum (ER) stress response. ATF4 also transcriptionally induces multiple effectors that determine cell fate depending on cellular context. In addition, ATF4 can communicate both pro-apoptotic and pro-survival signals. How ATF4 mediates its prosurvival roles, however, requires further investigation. Here, we report that the CDK inhibitor p21 is a novel target gene of ATF4. We identified two ATF4-responsive elements, one of which directly binds ATF4, within the first intron of the p21 gene. Importantly, overexpression of p21 enhances cell survival following ER stress induction, while p21 knockdown increases cell death. These results suggest that p21 induction plays a vital role in the cellular response to ER stress and indicate that p21 is a prosurvival effector of ATF4.

Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway

“…MCF7, HaCaT, TIG-3, and AT2KY cells were maintained in Dulbecco’s modified Eagle’s medium (Nacalai Tesque, Kyoto, Japan) supplemented with 4.5 g/L glucose, 10% fetal bovine serum (FBS) (Sigma, St. Louis, MO, USA), 100 U/mL of penicillin G, and 100 μg/mL of streptomycin as previously described [ 33 , 34 ]. PC3 cells were cultured in Roswell Park Memorial Institute 1640 medium (Nacalai Tesque) containing 10% FBS and penicillin/streptomycin.…”

Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence

“…H1299 (p53-null) cells were cultured in RPMI1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% (v/v) fetal bovine serum (FBS) (Sigma), penicillin G (100 units/mL) (Meiji Seika Pharma, Tokyo, Japan), and streptomycin (100 µg/mL) (Meiji Seika Pharma) at 37 • C in a 5% CO 2 incubator [23]. MCF7 (wild-type p53) cells, HCT116 (wild-type p53) cells, and TIG-1 (wild-type p53) cells were cultured in Dulbecco's modified Eagle's medium (DMEM) (Sigma) supplemented with 10% FBS, penicillin G (100 units/mL), and streptomycin (100 µg/mL) at 37 • C in a 5% CO 2 incubator [24].…”

“…The original constructs encoding human p53, p300, SIRT1 and β-galactosidase (β-gal) were described previously [16,25]. p53RE-Luc (pGL4/p53RE) and p21 promoter-Luc (pGL4/p21) have been described previously [23,25]. NOXA promoter-Luc (−198 to +45) was generated by ligating the human NOXA promoter region [26] with pGL4.10.…”

“…For apoptosis assay, both floating and attached cells were collected 48 h after Nutlin-3 treatment. Cells were then stained with Annexin V-FITC using the FITC Annexin V Apoptosis Detection Kit (BD Biosciences, Franklin Lakes, NJ, USA) [23]. SA-β-gal staining was performed as previously described [29].…”

Lysine-Specific Demethylase 1 (LSD1/KDM1A) Is a Novel Target Gene of c-Myc

“…18) They also demonstrated that LSD1 is a cofactor of the repressive function of N-Myc (c-Myc paralog). 19) Although LSD1 and c-Myc are both strongly expressed in human cancers, the mechanisms by which their activities are coordinated remain unclear. We herein demonstrated that LSD1 is a direct target gene of c-Myc.…”