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Tumor suppressor p53 as a therapeutic target in cancer – Klas Wiman's Team

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 is activated in response to DNA damage and oncogenic stress. Our goal is to understand the normal function of p53 and develop novel anticancer drugs that restore normal p53 function in tumors.

Klas G Wiman's research group consisting of six people.
Photo: N/A

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, Puma and Zmat3. 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.

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 identified the compound PRIMA-1 and the structural analog APR-246 (PRIMA-1Met) that induce cell death in TP53 mutant tumor cells and inhibit tumor growth in vivo in mice (Bykov et al. Nature Med. 2002; Bykov et al. Oncogene 2005). PRIMA-1 and APR-246 are converted to the active compound MQ, a Michael acceptor that binds covalently to cysteines in p53's core domain and enhances core domain thermostability (Lambert et al. Cancer Cell 2009; Zhang et al. Cell Death Dis. 2018). We have also found that APR-246, via MQ, can perturb redox homeostasis 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). APR-246 has been tested in several clinical trial sponsored by Aprea Therapeutics (Lehmann et al. J. Clin. Oncol. 2012; reviewed in Tuval et al. Nature Rev. Clin. Oncol. 2024). Moreover, we are developing novel therapy for tumors with TP53 nonsense mutation by pharmacological induction of translational readthrough. We have found that the 5-FU metabolite 5-fluorouridine induces readthrough and expression of fully active full-length p53 in tumor cells carrying R213X nonsense mutant TP53, resulting in apoptotic cell death (Palomar-Siles et al. Cell Death Dis. 2022).

Zmat3 (Wig-1), a p53-induced gene

Identification and characterization of novel p53 target 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).

Publications

Selected publications

  • Journal article: AMERICAN SOCIETY OF CLINICAL ONCOLOGY EDUCATIONAL BOOK / ASCO. AMERICAN SOCIETY OF CLINICAL ONCOLOGY. MEETING. 2025;45(3):e473616
    Shah PA; Wiman KG; Cichowski K; Rodon Ahnert J
  • Article: CELL REPORTS. 2024;43(10):114784
    Ramos AD; Liang YY; Surova O; Bacanu S; Gerault M-A; Mandal T; Ceder S; Langeback A; Osterroos A; Ward GA; Bergh J; Wiman KG; Lehmann S; Prabhu N; Loof S; Nordlund P
  • Review: NATURE REVIEWS CLINICAL ONCOLOGY. 2024;21(2):106-120
    Tuval A; Strandgren C; Heldin A; Palomar-Siles M; Wiman KG
  • Review: UPSALA JOURNAL OF MEDICAL SCIENCES. 2024;129:e10719
    Strandgren C; Wiman KG
  • Article: RNA BIOLOGY. 2023;20(1):368-383
    Heldin A; Cancer M; Palomar-Siles M; Ohlin S; Zhang M; Sun-Zhang A; Mariani A; Liu J; Bykov VJN; Wiman KGG
  • Article: PLOS ONE. 2023;18(11):e0292468
    Palomar-Siles M; Yurevych V; Bykov VJN; Wiman KG
  • Article: CELL DEATH & DISEASE. 2022;13(11):997
    Palomar-Siles M; Heldin A; Zhang M; Strandgren C; Yurevych V; van Dinter JT; Engels SAG; Hofman DA; Ohlin S; Meineke B; Bykov VJN; van Heesch S; Wiman KG
  • Article: CELL DEATH & DISEASE. 2022;13(3):214
    Zhang Q; Balourdas D-I; Baron B; Senitzki A; Haran TE; Wiman KG; Soussi T; Joerger AC
  • Article: CELL DEATH & DISEASE. 2021;12(7):709
    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
  • Article: EMBO MOLECULAR MEDICINE. 2021;13(2):e10852
    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
  • Article: CELL DEATH DISCOVERY. 2020;6(1):42
    Cheteh EH; Sarne V; Ceder S; Bianchi J; Augsten M; Rundqvist H; Egevad L; Ostman A; Wiman KG
  • Review: JOURNAL OF MOLECULAR CELL BIOLOGY. 2019;11(4):330-341
    Eriksson SE; Ceder S; Bykov VJN; Wiman KG
  • Article: CELL CHEMICAL BIOLOGY. 2018;25(10):1219-1230.e3
    Zhang Q; Bergman J; Wiman KG; Bykov VJN
  • Article: CELL DEATH & DISEASE. 2018;9(5):439
    Zhang Q; Bykov VJN; Wiman KG; Zawacka-Pankau J
  • Review: NATURE REVIEWS CANCER. 2018;18(2):89-102
    Bykov VJN; Eriksson SE; Bianchi J; Wiman KG
  • Article: CELL DEATH & DISEASE. 2017;8(6):e2848
    Cheteh EH; Augsten M; Rundqvist H; Bianchi J; Sarne V; Egevad L; Bykov VJN; Ostman A; Wiman KG
  • Article: NATURE COMMUNICATIONS. 2017;8:14844
    Liu DS; Duong CP; Haupt S; Montgomery KG; House CM; Azar WJ; Pearson HB; Fisher OM; Read M; Guerra GR; Haupt Y; Cullinane C; Wiman KG; Abrahmsen L; Phillips WA; Clemons NJ
  • Article: FRONTIERS IN ONCOLOGY. 2017;7:323
    Zhang M; Heldin A; Palomar-Siles M; Ohlin S; Bykov VJN; Wiman KG
  • Review: CELL DEATH AND DIFFERENTIATION. 2015;22(8):1239-1249
    Soussi T; Wiman KG
  • Article: CELL DEATH & DISEASE. 2015;6(6):e1794
    Mohell N; Alfredsson J; Fransson A; Uustalu M; Bystrom S; Gullbo J; Hallberg A; Bykov VJN; Bjorklund U; Wiman KG
  • Article: ONCOGENE. 2014;33(35):4407-4417
    Bersani C; Xu L-D; Vilborg A; Lui W-O; Wiman KG
  • Article: GENES & DEVELOPMENT. 2014;28(1):58-70
    Kelly GL; Grabow S; Glaser SP; Fitzsimmons L; Aubrey BJ; Okamoto T; Valente LJ; Robati M; Tai L; Fairlie WD; Lee EF; Lindstrom MS; Wiman KG; Huang DCS; Bouillet P; Rowe M; Rickinson AB; Herold MJ; Strasser A
  • Article: CELL DEATH & DISEASE. 2013;4(10):e881
    Peng X; Zhang M-Q; Conserva F; Hosny G; Selivanova G; Bykov VJN; Arner ESJ; Wiman KG
  • Article: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2013;110(6):2157-2162
    Shen J; van den Bogaard EH; Kouwenhoven EN; Bykov VJN; Rinne T; Zhang Q; Tjabringa GS; Gilissen C; van Heeringen SJ; Schalkwijk J; van Bokhoven H; Wiman KG; Zhou H
  • Article: JOURNAL OF CLINICAL ONCOLOGY. 2012;30(29):3633-3639
    Lehmann S; Bykov VJN; Ali D; Andren O; Cherif H; Tidefelt U; Uggla B; Yachnin J; Juliusson G; Moshfegh A; Paul C; Wiman KG; Andersson P-O
  • Article: CELL DEATH & DISEASE. 2012;3(4):e298
    Vilborg A; Bersani C; Wickstrom M; Segerstrom L; Kogner P; Wiman KG
  • Review: ONCOGENE. 2010;29(30):4245-4252
    Wiman KG
  • Article: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2009;106(37):15756-15761
    Vilborg A; Glahder JA; Wilhelm MT; Bersani C; Corcoran M; Mahmoudi S; Rosenstierne M; Grander D; Farnebo M; Norrild B; Wiman KG
  • Article: CANCER CELL. 2009;15(5):376-388
    Lambert JMR; Gorzov P; Veprintsev DB; Soderqvist M; Segerback D; Bergman J; Fersht AR; Hainaut P; Wiman KG; Bykov VJN
  • Review: CANCER CELL. 2007;12(4):303-312
    Soussi T; Wiman KG
  • Article: NATURE MEDICINE. 2002;8(3):282-288
    Bykov VJN; Issaeva N; Shilov A; Hultcrantz M; Pugacheva E; Chumakov P; Bergman J; Wiman KG; Selivanova G
  • Show more

Funding

  • Swedish Cancer Foundation
  • Swedish Research Council (VR)
  • Radiumhemmet Research Funds
  • Mayo Clinic Cancer Center & Cancer Research KI at ̽»¨¾«Ñ¡ (MCCC-KI) Cancer Research Award
  • Stiftelsen Bernt Katinas Minne
  • American Society of Hematology (ASH)

Dissertations

Angelos Heldin 
Pharmacological targeting of nonsense mutant TP53 and PTEN in cancer
Ph.D. 2023-10-20

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

Rabaiyat 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

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

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

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

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

Keywords:
Cancer and Oncology Cell and Molecular Biology Hematology
Content reviewer:
19-06-2025