Klas G Wiman's Group

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We perform research in molecular cell biology, tumor biology, and novel cancer therapy. Our main interest is the tumor suppressor p53, a DNA-binding transcription factor that accumulates in response to cellular stress, e.g. DNA damage and oncogene activation. Our goal is to understand the normal function and regulation of p53 in the context of tumor progression, and to create novel anticancer drugs that restore p53 function.

p53 activates transcription of target genes such as p21, Bax, Puma and Tigar, and regulates cellular processes such as cell cycle arrest, senescence, apoptosis, metabolism and autophagy. The p53 gene (TP53) is frequently mutated in cancer. Most TP53 mutations are missense mutations that disrupt p53's specific DNA binding and thereby inactivate normal p53 function. Many missense p53 mutants have also acquired gain-of-function (GOF) activities, e.g. complex formation with the p53 family protein p63. A smaller fraction of human tumors carry nonsense mutations in TP53 that result in a truncated non-functional p53 protein (see Soussi and Wiman, Cell Death & Differ. 2015 Aug;22(8):1239-49).

Reactivation of mutant p53: a novel strategy for cancer therapy

The frequent TP53-mutations in human tumors and the observation that p53 is usually expressed at high levels in tumors makes mutant p53 an attractive target for novel cancer therapy. We have identified the compound PRIMA-1 that restores wild type conformation to mutant p53, induces tumor cell apoptosis, and inhibits tumor growth in mice (Bykov et al., Nature Med. 2002 Mar;8(3):282-8). The structural analog APR-246 (PRIMA-1Met) is more potent and synergizes with cisplatin and other chemotherapeutic drugs. 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 (Lambert et al., Cancer Cell 2009 May;15(5):376-88). APR-246 has been tested in a phase I/IIa clinical trial sponsored by Aprea Therapeutics AB (Lehmann et al., J. Clin. Oncol. 2012 Oct;30(29):3633-9), and is currently tested in a phase II clinical trial in patients with ovarian cancer (see clinicaltrials.gov). We are screening chemical libraries for novel compounds that induce translational readthrough of nonsense mutant TP53 and expression of full length functional p53 protein in tumor cells. The project is supported by an Advanced ERC grant (TRANSREAD).

Wig-1 (Zmat3), a p53-induced gene that regulates mRNA stability

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 Wig-1 (Zmat3), located on human chromosome 3q26.3-27. Wig-1 encodes a conserved nuclear zinc finger protein with affinity for double stranded RNA. We found that Wig-1 binds to the 3'UTR of several mRNAs and regulates their stability, including p53 mRNA (Vilborg et al., PNAS 2009 Sep;106(37):15756-61) and N-Myc mRNA (Vilborg et al., Cell Death Dis. 2012 Apr;3():e298). Wig-1 also regulates p53 target mRNAs FAS/CD95 and 14-3-3sigma, and thereby influences cell cycle arrest and cell death (Bersani et al., Oncogene 2014 Aug;33(35):4407-17). The Wig-1 expression pattern correlates with patient survival in cervical cancer (Xu et al., PLoS ONE 2014;9(11):e111125). Our further work is focused on characterization of other Wig-1 target mRNAs and studies of the role of Wig-1 in vivo in mice carrying a conditional Wig-1 knock-out allele. 

Research grants

  • ERC Advanced grant
  • Childhood Cancer Fund
  • Radiumhemmet Research Funds
  • Swedish Cancer Fund
  • Swedish Research Council 

Group members

Klas G. Wiman, Professor, PI
Vladimir J.N. Bykov, Associate Professor
Sofi E. Eriksson, Post doc
Julie Bianchi, Post doc
Charlotte Strandgren, Post doc
Matko Cancer, Post doc
Emarndeena Haji Cheteh, PhD student
Sophia Ceder, PhD student
Mireia Palomar-Siles, PhD student
Angelos Heldin, PhD student
Susanne Öhlin, Technician

Dissertations

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-iduced 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

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

29670092

29242642

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

28569790

28348409

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

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

Expression of the p53 target Wig-1 is associated with HPV status and patient survival in cervical carcinoma.
Xu L, Muller S, Thoppe S, Hellborg F, Kanter L, Lerner M, et al
PLoS ONE 2014 ;9(11):e111125

Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.
Kelly G, Grabow S, Glaser S, Fitzsimmons L, Aubrey B, 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 L, Vilborg A, Lui W, Wiman K
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 M, Conserva F, Hosny G, Selivanova G, Bykov V, 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

23355676

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 V, 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 K
Cell Death Dis 2012 Apr;3():e298

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

The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element.
Vilborg A, Glahder J, Wilhelm M, 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 J, Gorzov P, Veprintsev D, 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 K
Cancer Cell 2007 Oct;12(4):303-12

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

Full list of publications