PKCε Promotes Oncogenic Functions of ATF2 in the Nucleus While Blocking Its Apoptotic Function at Mitochondria

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Feb 7

PMID 22304920

Citations 45

Authors

Eric Lau

Harriet Kluger

Tal Varsano

Kiyoung Lee

Immo Scheffler

David L Rimm

Trey Ideker

Zeev A Ronai

Affiliations

Soon will be listed here.

Abstract

The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.

Citing Articles

Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.

Yazaki J, Yamanashi T, Nemoto S, Kobayashi A, Han Y, Hasegawa T Biol Methods Protoc. 2024; 9(1):bpae039.

PMID: 38884001 PMC: 11180226. DOI: 10.1093/biomethods/bpae039.

Prohibitions in the meta-inflammatory response: a review.

Todosenko N, Yurova K, Vulf M, Khaziakhmatova O, Litvinova L Front Mol Biosci. 2024; 11:1322687.

PMID: 38813101 PMC: 11133639. DOI: 10.3389/fmolb.2024.1322687.

Spatially differential regulation of ATF2 phosphorylation contributes to warning coloration of gregarious locusts.

Kang X, Yang M, Cui X, Wang H, Kang L Sci Adv. 2023; 9(34):eadi5168.

PMID: 37611100 PMC: 10446495. DOI: 10.1126/sciadv.adi5168.

The FGFR2c/PKCε Axis Controls MCL-1-Mediated Invasion in Pancreatic Ductal Adenocarcinoma Cells: Perspectives for Innovative Target Therapies.

Ranieri D, French D, Persechino F, Guttieri L, Torrisi M, Belleudi F Biomedicines. 2022; 10(7).

PMID: 35884957 PMC: 9312859. DOI: 10.3390/biomedicines10071652.

The two-faced role of ATF2 on cisplatin response in gastric cancer depends on p53 context.

Xu L, Wang J, Zhang D, Song L, Wu H, Wang J Cell Biosci. 2022; 12(1):77.

PMID: 35641966 PMC: 9153165. DOI: 10.1186/s13578-022-00802-w.

References

Bhoumik A, Fichtman B, DeRossi C, Breitwieser W, Kluger H, Davis S . Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc Natl Acad Sci U S A. 2008; 105(5):1674-9. PMC: 2234203. DOI: 10.1073/pnas.0706057105. View

Fu X, Wan S, Lyu Y, Liu L, Qi H . Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS One. 2008; 3(4):e2009. PMC: 2329593. DOI: 10.1371/journal.pone.0002009. View

Xu L, Shen S, Hoshida Y, Subramanian A, Ross K, Brunet J . Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Mol Cancer Res. 2008; 6(5):760-9. PMC: 2756991. DOI: 10.1158/1541-7786.MCR-07-0344. View

Berger A, Kluger H, Li N, Kielhorn E, Halaban R, Ronai Z . Subcellular localization of activating transcription factor 2 in melanoma specimens predicts patient survival. Cancer Res. 2003; 63(23):8103-7. View

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P . p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003; 11(3):577-90. DOI: 10.1016/s1097-2765(03)00050-9. View

Nishikawa K, Toker A, Johannes F, Songyang Z, Cantley L . Determination of the specific substrate sequence motifs of protein kinase C isozymes. J Biol Chem. 1997; 272(2):952-60. DOI: 10.1074/jbc.272.2.952. View

Lopez-Bergami P, Lau E, Ronai Z . Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer. 2009; 10(1):65-76. PMC: 2874064. DOI: 10.1038/nrc2681. View

Koch U, Radtke F . Notch and cancer: a double-edged sword. Cell Mol Life Sci. 2007; 64(21):2746-62. PMC: 11136344. DOI: 10.1007/s00018-007-7164-1. View

Lee J, Kim C, Simon D, Aminova L, Andreyev A, Kushnareva Y . Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival. J Biol Chem. 2005; 280(49):40398-401. PMC: 2612541. DOI: 10.1074/jbc.C500140200. View

10.

Gupta S, Campbell D, Derijard B, Davis R . Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995; 267(5196):389-93. DOI: 10.1126/science.7824938. View

11.

Abu-Hamad S, Arbel N, Calo D, Arzoine L, Israelson A, Keinan N . The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins. J Cell Sci. 2009; 122(Pt 11):1906-16. DOI: 10.1242/jcs.040188. View

12.

Carvalho A, Sharpe J, Rosenstock T, Teles A, Youle R, Smaili S . Bax affects intracellular Ca2+ stores and induces Ca2+ wave propagation. Cell Death Differ. 2004; 11(12):1265-76. DOI: 10.1038/sj.cdd.4401508. View

13.

Shulga N, Wilson-Smith R, Pastorino J . Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism. Cell Cycle. 2009; 8(20):3355-64. PMC: 2829766. DOI: 10.4161/cc.8.20.9853. View

14.

Yu M, Zloty D, Cowan B, Shapiro J, Haegert A, Bell R . Superficial, nodular, and morpheiform basal-cell carcinomas exhibit distinct gene expression profiles. J Invest Dermatol. 2008; 128(7):1797-805. DOI: 10.1038/sj.jid.5701243. View

15.

Barrett L, Van Bockstaele E, Sul J, Takano H, Haydon P, Eberwine J . Elk-1 associates with the mitochondrial permeability transition pore complex in neurons. Proc Natl Acad Sci U S A. 2006; 103(13):5155-60. PMC: 1458810. DOI: 10.1073/pnas.0510477103. View

16.

Bhoumik A, Huang T, Ivanov V, Gangi L, Qiao R, Woo S . An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis. J Clin Invest. 2002; 110(5):643-50. PMC: 151112. DOI: 10.1172/JCI16081. View

17.

Larsson L, Henriksson M . The Yin and Yang functions of the Myc oncoprotein in cancer development and as targets for therapy. Exp Cell Res. 2010; 316(8):1429-37. DOI: 10.1016/j.yexcr.2010.03.025. View

18.

Gillespie S, Zhang X, Hersey P . Variable expression of protein kinase C epsilon in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis. Mol Cancer Ther. 2005; 4(4):668-76. DOI: 10.1158/1535-7163.MCT-04-0332. View

19.

Liu H, Deng X, Shyu Y, Li J, Taparowsky E, Hu C . Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. EMBO J. 2006; 25(5):1058-69. PMC: 1409714. DOI: 10.1038/sj.emboj.7601020. View

20.

Zalk R, Israelson A, Garty E, Azoulay-Zohar H, Shoshan-Barmatz V . Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria. Biochem J. 2004; 386(Pt 1):73-83. PMC: 1134768. DOI: 10.1042/BJ20041356. View