Bio

Honors & Awards


  • VR postdoctor fellowship, The Swedish Research Council (2012-2013)

Professional Education


  • Doctor of Philosophy, Karolinska Institutet (2010)

Stanford Advisors


Publications

Journal Articles


  • APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shen, J., van den Bogaard, E. H., Kouwenhoven, E. N., Bykov, V. J., Rinne, T., Zhang, Q., Tjabringa, G. S., Gilissen, C., van Heeringen, S. J., Schalkwijk, J., van Bokhoven, H., Wiman, K. G., Zhou, H. 2013; 110 (6): 2157-2162

    Abstract

    p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1(MET) (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.

    View details for DOI 10.1073/pnas.1201993110

    View details for Web of Science ID 000315209800046

    View details for PubMedID 23355676

  • PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73 ONCOGENE Rokaeus, N., Shen, J., ECKHARDT, I., Bykov, V. J., Wiman, K. G., Wilhelm, M. T. 2010; 29 (49): 6442-6451

    Abstract

    The low molecular weight compound PRIMA-1 and the structural analog PRIMA-1(MET), also named APR-246, reactivate mutant p53 through covalent binding to the core domain and induce apoptosis in tumor cells. Here, we asked whether PRIMA-1(MET)/APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. We found that PRIMA-1(MET)/APR-246 can restore the pro-apoptotic function to mutant TAp63? and TAp73? in tumor cells but has less effect on TAp73?. Moreover, PRIMA-1(MET)/APR-246-stimulated DNA binding of mutant TAp63? and induced expression of the p53/p63/p73 downstream targets p21 and Noxa. The reactivation of mutant p53, p63 and p73 by PRIMA-1(MET)/APR-246 indicates a common mechanism, presumably involving homologous structural elements in the p53 family proteins. Our findings may open avenues for therapeutic intervention in human developmental disorders with mutations in p63.

    View details for DOI 10.1038/onc.2010.382

    View details for Web of Science ID 000285138900004

    View details for PubMedID 20818419

  • PRIMA-1(MET) induces mitochondrial apoptosis through activation of caspase-2 ONCOGENE Shen, J., Vakifahmetoglu, H., Stridh, H., Zhivotovsky, B., Wiman, K. G. 2008; 27 (51): 6571-6580

    Abstract

    p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1(MET) reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1(MET) induces mutant p53-dependent mitochondria-mediated apoptosis through activation of caspase-2 with subsequent cytochrome c release and further activation of downstream caspase-9 and caspase-3. Inhibition of caspase-2 by a selective inhibitor and/or siRNA prevents cytochrome c release on PRIMA-1(MET) treatment and causes a significant reduction in PRIMA-1(MET)-induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1(MET) that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1(MET)-based anticancer drugs.

    View details for DOI 10.1038/onc.2008.249

    View details for Web of Science ID 000260501700004

    View details for PubMedID 18663359

  • Mutant p53 targeting by the low molecular weight compound STIMA-1 MOLECULAR ONCOLOGY Zache, N., Lambert, J. M., Rokaeus, N., Shen, J., Hainaut, P., Bergman, J., Wiman, K. G., Bykou, V. N. 2008; 2 (1): 70-80

    Abstract

    Reactivation of mutant p53 in human tumor cells should induce cell death by apoptosis and thus eliminate the tumor. Several small molecules that reactivate mutant p53 have been identified. Here we show that STIMA-1, a low molecular weight compound with some structural similarities to the previously identified molecule CP-31398, can stimulate mutant p53 DNA binding in vitro and induce expression of p53 target proteins and trigger apoptosis in mutant p53-expressing human tumor cells. Human diploid fibroblasts are significantly more resistant to STIMA-1 than mutant or wild type p53-carrying tumor cells. STIMA-1 may provide new insights into possible mechanisms of mutant p53 reactivation and thus facilitate the development of novel anticancer drugs that target mutant p53-carrying tumors.

    View details for DOI 10.1016/j.molonc.2008.02.004

    View details for Web of Science ID 000264061800011

    View details for PubMedID 19383329

  • Analysis of T-cell responses in malaria-exposed and non-exposed donors using Plasmodium falciparum asexual blood stages enriched by a simple centrifugation method ACTA TROPICA Farouk, S. E., Shen, J., Tangteerawatana, P., Bolad, A., Berzins, K., Troye-Blomberg, M. 2006; 97 (1): 42-49

    Abstract

    Several studies have reported on similar in vitro cellular responses to different malaria-antigen preparations in both malaria-primed and un-primed donors. Whether intact live parasites can exert a distinct type of response in either of the two groups is not well known. In this study, we developed a simple three-step centrifugation method for simultaneous enrichment of early and late blood stages from Plasmodium falciparum cultures. Such enriched P. falciparum fractions and other antigen preparations were used to stimulate lymphocytes from malaria-exposed and non-exposed individuals to examine the proliferative activity and expansion of CD3+, gammadelta+, CD4+, and CD8+ T cells. While lymphocytes from malaria non-exposed donors proliferated relatively higher than those from malaria-exposed donors in response to most antigens tested, the enriched fractions of live parasites exerted higher proliferative responses on cells from the latter donors. This suggests the existence of memory cells in the malaria-exposed donors, but not in the non-exposed ones. Flow cytometric analysis revealed a higher percentage expansion of CD4+ T cells in the responding cells of the exposed donors than the non-exposed ones. Taken together, this study reports on a simple method that simultaneously enriches for intact live early and late blood stages of P. falciparum parasites. Moreover, the study revealed higher expansion CD4+ T cells in the exposed individuals than the non-exposed in response to live malaria parasites and not to other parasite-antigen preparations.

    View details for DOI 10.1016/j.actatropica.2005.08.007

    View details for Web of Science ID 000234534300007

    View details for PubMedID 16280120

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