Klas G Wiman's Group

The tumor suppressor gene TP53

The p53 protein regulates cellular processes such as cell cycle progression, apoptosis and metabolism through transcriptional transactivation of target genes, e.g. p21, Bax and Puma. The TP53  gene is mutated in around half of all tumors. Most TP53 mutations are missense mutations that disrupt p53's specific DNA binding and transcriptional transactivation activity. A smaller fraction of human tumors carry TP53 nonsense mutations that result in a truncated non-functional p53 protein (see Soussi & Wiman, Cell Death Differ. 2015).

Reactivation of mutant p53: a novel strategy for cancer therapy

The high frequency of TP53-mutations in human tumors makes mutant p53 an interesting target for novel cancer therapy. We have identified the compound PRIMA-1 and the structural analog APR-246 (PRIMA-1Met) that induce apoptosis in TP53 mutant tumor cells and inhibit tumor growth in vivo in mice (Bykov et al. Nature Med. 2002; Bykov et al. Oncogene 2005). Both PRIMA-1 and APR-246 are converted to the active compound MQ, a Michael acceptor that binds covalently to cysteines in the p53 core domain and enhances thermostability of the protein (Lambert et al. Cancer Cell 2009; Zhang et al. Cell Death Dis. 2018). We have also found that APR-246, via MQ, can affect the redox balance in cells, for example by inhibition of thioredoxin reductase and binding and depletion of glutathione (Peng et al. Cell Death Dis. 2013; Mohell et al. Cell Death Dis. 2015; Ceder et al. EMBO Mol. Med. 2021). These redox effects probably contribute to tumor cell death. The substance synergizes with cisplatin and other chemotherapeutic drugs. APR-246 has been tested in several clinical trial sponsored by Aprea Therapeutics (Lehmann et al. J. Clin. Oncol. 2012; ClinicalTrials.gov; aprea.com). We are also characterizing compunds that can induce translational readthrough of nonsense mutant TP53 and restore expression of full length functional p53 protein in tumor cells (Palomar-Siles et al. Cell Death Dis. 2022).

Zmat3 (Wig-1) a p53-induced gene

Identification and characterization of novel p53-regulated genes is important in order to understand the p53 pathway and p53-mediated tumor suppression. We identified the p53 target gene Zmat3 (Wig-1), located on human chromosome 3q26.3-27 (Varmeh-Ziaie et al. Oncogene 1997; Hellborg et al. Oncogene 2001). Zmat3 encodes a conserved zinc finger protein with affinity for double stranded RNA (Mendez-Vidal et al. Nucl. Acids Res. 2002). Our results suggest that Zmat3 directs the p53 response towards cell cycle arrest by regulation of specific p53 target genes at the mRNA level (Bersani et al. Oncogene 2014). Further studies are focused on the role of Zmat3 in vivo in mice carrying a conditional Zmat3 knock-out allele.

Research grants

• Swedish Cancer Fund
• Swedish Research Council
• Childhood Cancer Fund
• Radiumhemmet Research Funds
• Mayo Clinic Cancer Center & Cancer Research KI at Karolinska Institutet (MCCC-KI) Cancer Research Award
• Stiftelsen Bernt Katinas Minne

Group members

Klas G. Wiman, Professor, PI
Susanne Öhlin, Technician, lab manager
Charlotte Strandgren, Post doc
Amos Tuval, Post doc
Angelos Heldin, PhD student

Dissertations

Mireia Palomar Siles
Translational readthrough of nonsense mutant TP53, RB1 and PTEN tumor suppressor genes as a strategy for novel cancer therapy
Ph.D. 2023-03-31
Abstract and thesis

Sophia Ceder
Mechanisms of cancer cell death by mutant p53-reactivating compound APR-246
Ph.D. 2021-03-05
Abstract and thesis

Emarndeena H. Cheteh
p53 and cancer-associated fibroblasts: implications for cancer therapy and drug resistance
Ph.D. 2020-10-26
Abstract and thesis

Meiqiongzi Zhang
Making sense from nonsense and missense: pharmacological rescue of mutant tumor suppressor p53
Ph.D. 2018-06-20
Abstract and thesis

Qiang Zhang
Understanding p53 structure and targeting mutant p53 for improved cancer therapy
Ph.D. 2018-06-15
Abstract and thesis

Harsha Madapura Sekharappa
Regulatory mechanisms contributing to the homeostasis of normal and malignant hematopoietic cells
Ph.D. 2016-05-11
Abstract and thesis

Lidi Xu
The p53-induced Wig-1 protein: identification of mRNA targets and role as survival factor in development and cancer
Ph.D. 2015-12-02
Abstract and thesis

Cinzia Bersani
The role of the RNA-binding protein Wig-1 in post-transcriptional regulation of gene expression
Ph.D. November 14, 2014
Abstract and thesis

Nina Rökaeus
Pharmacological targeting of mutant p53 family members
Ph.D. May 12, 2011
Abstract and thesis

Salah Mahmoudi
WRAP53 unwrapped; roles in nuclear architecture and cancer
Ph.D. Feb. 4, 2011
(Main supervisor: Marianne Farnebo)
Abstract and thesis

Jinfeng Shen
Rescue of mutant p53 family members by the low molecular weight compound PRIMA-1MET/APR-246
Ph.D. Dec. 3, 2010
(Main supervisor: Vladimir Bykov)
Abstract and thesis

Anna Vilborg
Wig-1: A p53 target that regulates the mRNA of p53 and Myc - and more?
Ph.D. Oct. 15, 2010
Abstract and thesis

Jeremy Lambert
Mutant p53 reactivation by prima-1 : Molecular mechanism and biological effects
Ph.D. Dec. 5, 2008
Abstract and thesis

Magdalena Prahl
The p53-induced Wig-1 protein: Studies of interaction partners and expression in tumor
Ph.D. Sept. 25, 2008
Abstract and thesis

Nicole Zache
Studies of mutant p53-targeting small molecules
Ph.D. Nov. 30, 2007
Abstract and thesis

Rubayat Rahman-Roblick
The P53 pathway : role of telomerase and identification of novel targets : acts of a master regulator of tumor suppression.
Ph.D. June 7, 2007
Abstract and thesis

Fredrik Hellborg
Identification, cloning and characterization of the p53-induced gene human wig-1
Ph.D. Dec. 17, 2004
Abstract

Mikael Lindström
Functional characterization of the alternative reading frame protein p14ARF
Ph.D. May 27, 2004
Abstract and thesis

Margareta T. Wilhelm
The p53-induced gene Wig-1: regulation of expression and role in embryonic development
Ph.D. Dec. 12, 2003
Abstract

Cristina Mendez-Vidal
Molecular studies of Wig-1, a p53-induced zinc finger protein
Ph.D. Dec. 5, 2003
Abstract

Selected publications

Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine.
Palomar-Siles M, Heldin A, Zhang M, Strandgren C, Yurevych V, van Dinter JT, Engels SAG, Hofman DA, Öhlin S, Meineke B, Bykov VJN, van Heesch S, Wiman KG
Cell Death Dis 2022 Nov;13(11):997

Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells.
Ceder S, Eriksson SE, Liang YY, Cheteh EH, Zhang SM, Fujihara KM, Bianchi J, Bykov VJN, Abrahmsen L, Clemons NJ, Nordlund P, Rudd SG, Wiman KG
Cell Death Dis 2021 07;12(7):709

Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog.
Zhang Q, Balourdas DI, Baron B, Senitzki A, Haran TE, Wiman KG, Soussi T, Joerger AC
Cell Death Dis 2022 03;13(3):214

A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.
Ceder S, Eriksson SE, Cheteh EH, Dawar S, Corrales Benitez M, Bykov VJN, Fujihara KM, Grandin M, Li X, Ramm S, Behrenbruch C, Simpson KJ, Hollande F, Abrahmsen L, Clemons NJ, Wiman KG
EMBO Mol Med 2021 02;13(2):e10852

p53 as a hub in cellular redox regulation and therapeutic target in cancer.
Eriksson SE, Ceder S, Bykov VJN, Wiman KG
J Mol Cell Biol 2019 04;11(4):330-341

Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells.
Cheteh EH, Sarne V, Ceder S, Bianchi J, Augsten M, Rundqvist H, et al
Cell Death Discov 2020 ;6():42

Role of Thiol Reactivity for Targeting Mutant p53.
Zhang Q, Bergman J, Wiman K, Bykov V
Cell Chem Biol 2018 Oct;25(10):1219-1230.e3

APR-246 reactivates mutant p53 by targeting cysteines 124 and 277.
Zhang Q, Bykov V, Wiman K, Zawacka-Pankau J
Cell Death Dis 2018 05;9(5):439

Targeting mutant p53 for efficient cancer therapy.
Bykov VJN, Eriksson SE, Bianchi J, Wiman KG
Nat. Rev. Cancer 2018 02;18(2):89-102

Synergistic Rescue of Nonsense Mutant Tumor suppressor p53 by Combination Treatment with Aminoglycosides and Mdm2 Inhibitors.
Zhang M, Heldin A, Palomar-Siles M, Öhlin S, Bykov V, Wiman K
Front Oncol 2018 Jan 4;7:323

Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death.
Cheteh E, Augsten M, Rundqvist H, Bianchi J, Sarne V, Egevad L, et al
Cell Death Dis 2017 06;8(6):e2848

Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation.
Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, et al
Nat Commun 2017 03;8():14844

APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells.
Mohell N, Alfredsson J, Fransson Å, Uustalu M, Byström S, Gullbo J, et al
Cell Death Dis 2015 Jun;6():e1794

TP53: an oncogene in disguise.
Soussi T, Wiman KG
Cell Death Differ. 2015 Aug;22(8):1239-49

Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.
Kelly GL, Grabow S, Glaser SP, Fitzsimmons L, Aubrey BJ, Okamoto T, et al
Genes Dev. 2014 Jan;28(1):58-70

Wig-1 regulates cell cycle arrest and cell death through the p53 targets FAS and 14-3-3σ.
Bersani C, Xu LD, Vilborg A, Lui WO, Wiman KG
Oncogene 2014 Aug;33(35):4407-17

APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase.
Peng X, Zhang MQ, Conserva F, Hosny G, Selivanova G, Bykov VJ, et al
Cell Death Dis 2013 Oct;4():e881

p53 in the Clinics; Hainaut P, Olivier M, Wiman KG. Editors; Springer, New York 2013. ISBN 978-1-4614-3675-1

APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations.
Shen J, van den Bogaard EH, Kouwenhoven EN, Bykov VJ, Rinne T, Zhang Q, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Feb;110(6):2157-62

Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer.
Lehmann S, Bykov VJ, Ali D, Andrén O, Cherif H, Tidefelt U, et al
J. Clin. Oncol. 2012 Oct;30(29):3633-9

Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth.
Vilborg A, Bersani C, Wickström M, Segerström L, Kogner P, Wiman KG
Cell Death Dis 2012 Apr;3():e298

Pharmacological reactivation of mutant p53: from protein structure to the cancer patient.
Wiman KG
Oncogene 2010 Jul;29(30):4245-52

The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element.
Vilborg A, Glahder JA, Wilhelm MT, Bersani C, Corcoran M, Mahmoudi S, et al
Proc. Natl. Acad. Sci. U.S.A. 2009 Sep;106(37):15756-61

PRIMA-1 reactivates mutant p53 by covalent binding to the core domain.
Lambert JM, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J, et al
Cancer Cell 2009 May;15(5):376-88

Shaping genetic alterations in human cancer: the p53 mutation paradigm.
Soussi T, Wiman KG
Cancer Cell 2007 Oct;12(4):303-12

Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.
Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al
Nat. Med. 2002 Mar;8(3):282-8

Full list of publications