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IER5 Is a p53-Regulated Activator of HSF1 That Contributes to Promotion of Cancer

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Heat Shock Proteins in Signaling Pathways

Part of the book series: Heat Shock Proteins ((HESP,volume 17))

Abstract

The p53 gene is one of the most frequently mutated genes in human cancer and functions as a tumor suppressor and transcriptional factor that regulates various genes involved in cancer. One p53 target gene is IER5, whose function was initially unknown, but we have shown facilitates the activation of the transcriptional activator HSF1 by recruiting the PP2A phosphatase to HSF1, leading to its hypo-phosphorylation and activation. HSF1 is the master transcriptional regulator of the HSP genes, which encode molecular chaperones essential for cellular homeostasis. HSP also exhibit anti-apoptotic functions by repressing pro-apoptotic factors, thereby protecting stressed cells from cell death. Although HSF1-HSP pathway is generally activated by cellular stress such as heat shock, this pathway is also hyperactivated in cancers independent of heat shock and contribute to promotion of cancer development and resistance to cancer treatments. We observed that IER5 is overexpressed in several cancers in a p53-independent manner and contributes to tumor malignancy via activation of the HSF1-HSP pathway. We propose a model in which IER5 activates HSF1 in cancer as part of the p53-IER5-HSF1-HSP pathway, thereby providing stress resistance to cancer cells. This section briefly reviews the roles of HSF1, HSP, p53 and IER5.

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Abbreviations

4C-seq:

circular chromatin conformation capture sequencing

ABC:

ATP binding cassette

ABCB1:

ATP-binding cassette sub-family B member 1

AIF:

apoptosis-inducing factor

Apaf-1:

apoptosis protease activating factor 1

ASK1:

apoptosis signal regulating kinase 1

BAG3:

Bcl-2-associated athanogene domain 3

Bax:

Bcl-2-associated X protein

CAD:

caspase activated DNase

ChIP-seq:

chromatin immunoprecipitation sequencing

GOF:

gain-of-function

HSEs:

heat shock elements

HSF1:

heat shock factor 1

HSP:

heat shock proteins

ICAD:

inhibitor of CAD

IER5:

immediate early gene response 5

LFS:

Li-Fraumeni syndrome

MDM2:

murine double minute 2

MDR:

multidrug resistance

MDR-1:

multidrug resistance protein 1

Pgp:

P-glycoprotein

PP2A:

protein phosphatase 2A

PTEN:

phosphatase and tensin homolog

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Acknowledgements

We thank Marc Lamphier for critical reading of the manuscript. This study was partly supported by a Grant-in-Aid for Scientific Research (B) (#17H03587) (R.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Development of Innovative Research on Cancer Therapeutics (P-DIRECT)/Ministry of Education, Culture, Sports, Science and Technology of Japan (R.O.), research grants from Research Grant of the Princess Takamatsu Cancer Research Fund (R.O.), the Mitsubishi Foundation (to R.O.), the NOVARTIS Foundation (Japan) for the Promotion of Science (to R.O.), the Project Mirai Cancer Research Grants (R.O.), the Okinaka Memorial Institute for Medical Research (to R.O.), the National Cancer Center Research and Development Fund (to R.O., 29-E-2), the Life Science Foundation of Japan (to R.O.), and Foundation for Promotion of Cancer Research in Japan (to R.O.).

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Authors and Affiliations

  1. Unit 1, Candidate Discovery Science Laboratory, Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan

    Tatsuya Kawase

  2. Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tokyo, Japan

    Tatsuya Kawase, Yu Chen & Rieko Ohki

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  1. Tatsuya Kawase
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  2. Yu Chen
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  3. Rieko Ohki
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Correspondence to Rieko Ohki .

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Editors and Affiliations

  1. Professor, Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Kawase, T., Chen, Y., Ohki, R. (2019). IER5 Is a p53-Regulated Activator of HSF1 That Contributes to Promotion of Cancer. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins in Signaling Pathways. Heat Shock Proteins, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-030-03952-3_13

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