Nucleophosmin (NPM1/B23) Interacts with Activating Transcription Factor 5 (ATF5) Protein and Promotes Proteasome- and Caspase-dependent ATF5 Degradation in Hepatocellular Carcinoma Cells

Abstract

Background: NPM1 promotes whereas ATF5 inhibits HCC proliferation; NPM1 and ATF5 are regulated in an opposite manner in normal hepatocytes and HCC. Results: NPM1 competes against HSP70 for ATF5 binding and promotes proteasome-and caspase-dependent ATF5 protein degradation. Conclusion: NPM1 is a novel ATF5-interacting protein and abrogates ATF5 function in HCC. Significance: We reveal a mechanism by which NPM1 promotes HCC proliferation and survival via regulation of ATF5.

SUMO2/3 modification of activating transcription factor 5 (ATF5) controls its dynamic translocation at the centrosome

“…DNA constructs expressing ATF5 full length, ATF5(1-100), ATF5(101-207), ATF5(148-281), ATF5(208-281), and ATF5(K29R) are described previously (8,12,24,25). ATF5(K106R/K107R), ATF5(ΔK212/213), and ATF5(K106R/K107R;ΔK212/213) were created using GFP-ATF5 as template and a QuikChange Site-Directed Mutagenesis Kit (Strategene) as described previously (9).…”

Cell Type-Dependent Function of Atf5: Where We Go from Here

“…The activating transcription factor 5 (ATF5 or ATFx) is a member of the ATF/CREB transcription factor family. Although ATF5 is known to regulate cell cycle progression [4][5][6][7], cell survival [5][6][7][8][9][10][11][12][13], autophagy [14], cell fate determination [15][16][17] and cellular stress response [13][14][15][16][17][18][19], and it is likely involved in the development of schizophrenia [20][21][22] and chronic lymphocytic leukemia [23], only a few of its targets have been reported and the mechanism of ATF5 function remains largely unknown and occasionally controversial.Previous reports have shown that ATF5 enhances cell survival and proliferation of glioma, breast cancer cells and neuroprogenitor cells [5,[10][11][12]24] while eliciting a G2/M blockade in hepatocellular carcinoma cells [4,6]. ATF5 acts as a pro-survival factor in HeLa and hematopoietic FL5.12 cells [8] but may also increase cisplatin-induced apoptosis through up-regulation of cyclin D3 in HeLa cells [25].…”

“…The activating transcription factor 5 (ATF5 or ATFx) is a member of the ATF/CREB transcription factor family. Although ATF5 is known to regulate cell cycle progression [4][5][6][7], cell survival [5][6][7][8][9][10][11][12][13], autophagy [14], cell fate determination [15][16][17] and cellular stress response [13][14][15][16][17][18][19], and it is likely involved in the development of schizophrenia [20][21][22] and chronic lymphocytic leukemia [23], only a few of its targets have been reported and the mechanism of ATF5 function remains largely unknown and occasionally controversial.…”

“…Previous reports have shown that ATF5 enhances cell survival and proliferation of glioma, breast cancer cells and neuroprogenitor cells [5,[10][11][12]24] while eliciting a G2/M blockade in hepatocellular carcinoma cells [4,6]. ATF5 acts as a pro-survival factor in HeLa and hematopoietic FL5.12 cells [8] but may also increase cisplatin-induced apoptosis through up-regulation of cyclin D3 in HeLa cells [25].…”

“…Significant downstream targets known to be regulated by ATF5 include stressrelated genes asparagine synthase [29,30] ATF5 expression is induced in response to various forms of cellular stress including Endoplasmic Reticulum (ER) stress [33,34], arsenite exposure [18,34], and amino acid limitation [18,27], among others. ATF5 is known to subject to multilayered regulation that includes transcriptional regulation by EBF1 [35], translational regulation that is controlled by phosphorylated eIF2 [19,34], and post-translational regulation that involves phosphorylation [26], acetylation [5], and ubiquitin-mediated [6,7,13,36,37] and caspase-mediated proteolysis [6,13]. We found that ATF5 is an extremely unstable protein with a half-life of about 1 h in HeLa, C6 and MCF-7 cells and that both chaperone proteins HSP70 and NPM1 are involved in regulating ATF5 protein stability [6,13].…”