Klas G Wiman's Group

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p53, Wig-1 and PRIMA-1/APR-246. Our research is focused on p53, a key tumor suppressor that is mutated in around 50% of all human tumors. Our goal is to understand the normal function and regulation of p53 in the context of tumor progression, and to design novel anticancer drugs that restore p53 function.

We perform research in molecular cell biology, tumor biology, and novel cancer therapy. Our main area of interest is the tumor suppressor p53, a DNA-binding transcription factor that accumulates in response to cellular stress, for instance DNA damage and oncogene activation. p53 triggers transcriptional transactivation of p53 target genes, such as p21, Bax, Puma and Fas/CD95, followed by cell cycle arrest, senescence and/or cell death by apoptosis. This serves to eliminate incipient tumor cells. However, p53 is frequently mutated in cancer, in most cases by missense mutations that disrupt specific DNA binding and thus inactivate normal p53 function (see Soussi and Wiman, Cancer Cell 12, 303-312, 2007).

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

Many mutations also endow mutant p53 with so called gain-of-function (GOF) activities, e.g. illegitimate regulation of genes that promote cell growth or survival, or complex formation with the p53 family proteins p63 and p73. Therefore, many mutant p53 alleles can be regarded as oncogenes whose activity is essential for sustained neoplastic growth.

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

Identification and characterization of novel p53-regulated genes is essential in order to improve the understanding of the p53 pathway, including regulation of p53 itself. We previously identified the p53 target gene Wig-1, located on human chromosome 3q26.3-27. Wig-1 encodes a highly conserved nuclear zinc finger protein with high affinity for double stranded RNA. We found that Wig-1 binds to the 3'UTR of p53 mRNA and enhances its stability, forming a positive regulatory loop that maintains high levels of p53 (Vilborg et al., PNAS 106, 15756-61, 2009).

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

Our work is currently aimed at identification and characterization of other Wig-1 target mRNAs, and a better understanding of how Wig-1 binding to 3'UTRs may regulate mRNA stability and possibly also translation. Also, the expression of Wig-1 in stem cells and various tumor cells is being investigated.

Reactivation of mutant p53: a novel strategy for cancer therapy

The fact that p53 is frequently mutated in human tumors and usually expressed at high levels, and that mutant p53-expressing tumors often respond poorly to conventional therapy, makes mutant p53 an attractive target for novel cancer therapy. We have previously identified PRIMA-1, a low molecular weight compound that restores wild type conformation to mutant p53, induces tumor cell apoptosis, and inhibits tumor growth in vivo in mice upon systemic administration (Bykov et al., Nature Med. 8, 282-288, 2002).

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

The structural analog PRIMA-1MET or APR-246 is even more potent and synergizes with cisplatin and other chemotherapeutic drugs. Both PRIMA-1 and PRIMA-1MET/APR-246 are converted to the active compound MQ, a Michael acceptor that covalently modifies cysteines in the p53 core domain. We have shown that modification by MQ per se is sufficient to reactivate mutant p53, and that it may also reactivate unfolded wild type p53 (Lambert et al., Cancer Cell 15, 376-388, 2009).

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

APR-246 has been tested in a phase I/II clinical trial sponsored by Aprea AB (Lehmann et al., J. Clin. Oncol. 30, 3633-3639, 2012).

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

Funding

Group members

Klas G. Wiman, MD, PhD, Professor, Group Leader
Vladimir Bykov, MD PhD, Associate Professor
Helene Wahlstedt, post doc
Sofi Eriksson, post doc
Julie Bianchi, post doc
Emarndeena Haji Cheteh, PhD student
Meiqiongzi Zhang, PhD student
Qiang Zhang, PhD student
Sophia Ceder, PhD student
Mireia Palomar, PhD student
Angelos Heldin, PhD student
Susanne Öhlin, Biomedical scientist

Dissertations

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

Retraction: PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2
Shen J, Vakifahmetoglu H, Stridh H, Zhivotovsky B, Wiman KG
Oncogene 2008 Nov 20;27(51):6571-80
Corrigendum Oncogene 2016 Jul 4

Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer.
Fransson , Glaessgen D, Alfredsson J, Wiman K, Bajalica-Lagercrantz S, Mohell N
J Ovarian Res 2016 May;9(1):27

Targeting of Mutant p53 and the Cellular Redox Balance by APR-246 as a Strategy for Efficient Cancer Therapy.
Bykov V, Zhang Q, Zhang M, Ceder S, Abrahmsen L, Wiman K
Front Oncol 2016 ;6():21

Genome-wide identification of Wig-1 mRNA targets by RIP-Seq analysis.
Bersani C, Huss M, Giacomello S, Xu L, Bianchi J, Eriksson S, et al
Oncotarget 2016 Jan;7(2):1895-911

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma.
Liu D, Read M, Cullinane C, Azar W, Fennell C, Montgomery K, et al
Gut 2015 Oct;64(10):1506-16

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

26024390

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

Mutant p53 reactivation by small molecules makes its way to the clinic.
Bykov V, Wiman K
FEBS Lett. 2014 Aug;588(16):2622-7

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 talks to PARP: the increasing complexity of p53-induced cell death.
Wiman K
Cell Death Differ. 2013 Nov;20(11):1438-9

p53 in the Clinics”; Hainaut, P., Olivier, M., and Wiman, K.G., 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 E, Kouwenhoven E, Bykov V, Rinne T, Zhang Q, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Feb;110(6):2157-62

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET.
Shalom-Feuerstein R, Serror L, Aberdam E, Müller F, van Bokhoven H, Wiman K, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Feb;110(6):2152-6

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

The p53 target Wig-1: a regulator of mRNA stability and stem cell fate?
Vilborg A, Bersani C, Wilhelm M, Wiman K
Cell Death Differ. 2011 Sep;18(9):1434-40

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

Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.
Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman K, Farnebo M
Mol. Cell 2009 Feb;33(4):462-71

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

p53 targets identified by protein expression profiling.
Rahman-Roblick R, Roblick U, Hellman U, Conrotto P, Liu T, Becker S, et al
Proc. Natl. Acad. Sci. U.S.A. 2007 Mar;104(13):5401-6

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis.
Liu T, Laurell C, Selivanova G, Lundeberg J, Nilsson P, Wiman K
Cell Death Differ. 2007 Mar;14(3):411-21

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

Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain.
Selivanova G, Iotsova V, Okan I, Fritsche M, Ström M, Groner B, et al
Nat. Med. 1997 Jun;3(6):632-8

Full list of publications