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p73 supports cellular growth through c-Jun-dependent AP-1 transactivation

Nature Cell Biology volume 9, pages 698–706 (2007)Cite this article

Abstract

The cause or consequence of overexpression of p73 (refs 1, 2), the structural and functional homologue of the tumour-suppressor gene product p53 (refs 3, 4), in human cancers is poorly understood. Here, we report a role for p73 in supporting cellular growth through the upregulation of AP-1 transcriptional activity. p73 suppresses growth when overexpressed alone, but synergises with the proto-oncogene c-Jun to promote cellular survival. Conversely, silencing of p73 expression compromises cellular proliferation. Molecular analysis revealed that expression of the AP-1 target-gene product cyclinD1 (ref. 5) is reduced concomitant with p73, but not p53, silencing. Moreover, cyclinD1 was induced by p73 expression in a c-Jun-dependent manner, and was required for p73-mediated cell survival. Furthermore, c-Jun-dependent AP-1 transcriptional activity was augmented by p73 and, consistently, induction of endogenous AP-1 target genes was compromised in the absence of p73. Chromatin immunoprecipitation and electrophoretic mobility shift analysis indicated that p73 enhanced the binding of phosphorylated c-Jun and Fra-1, another AP-1 family member, to AP-1 consensus DNA sequences, by regulating c-Jun phosphorylation and Fra-1 expression. Collectively, our data demonstrates a novel and unexpected role of p73 in augmenting AP-1 transcriptional activity through which it supports cellular growth.

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Figure 1: p73 supports cellular growth.
Figure 2: p73 activates cyclin D1, which is required for p73-mediated cellular growth.
Figure 3: p73 regulates AP-1 activity in a c-Jun-dependent manner, and is required for efficient AP-1 activation.
Figure 4: p73 potentiates the binding of phosphorylated c-Jun and Fra-1 to AP-1 consensus DNA sequences.
Figure 5: p73 regulates c-Jun phosphorylation and activates AP-1 activity in a JNK-independent manner.

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Acknowledgements

We thank K. W. Lin for technical assistance. We are grateful to A. Behrens, D. Bohmann, G. Blandino, M. Levrero, G. Melino, G. Del Sal and E. Passegue for the various plasmids, and to J. Wang, P. Sicinski and A. Behrens for the p73−/− fibroblasts, the cyclinD1+/+ and cyclinD1−/− cells and the junAA cells, respectively. F.V. is a visiting Scientist from Institute Cytology, St.Petersburg. This study was supported by grants from the National Medical Research Council and Biomedical Research Council of Singapore to K.S.

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Authors and Affiliations

  1. Laboratory of Molecular Carcinogenesis, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore

    Faina Vikhanskaya, Wen Hong Toh, Iqbal Dulloo & Kanaga Sabapathy

  2. Genome Institute of Singapore, Biopolis, Singapore, 138672, Singapore

    Qiang Wu & Huck Hui Ng

  3. Department of Physiology, National University of Singapore, 10, Kent Ridge Crescent, Singapore, 119260, Singapore

    Lakshmanane Boominathan

  4. Department of Biological Sciences, National University of Singapore, 10, Kent Ridge Crescent, Singapore, 119260, Singapore

    Huck Hui Ng

  5. Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, G61 1BD, Glasgow, UK

    Karen H. Vousden

  6. Department of Biochemistry, National University of Singapore, 10, Kent Ridge Crescent, Singapore, 119260, Singapore

    Kanaga Sabapathy

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  1. Faina Vikhanskaya
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  8. Kanaga Sabapathy
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Contributions

F.V. performed most of the experimental work presented in the paper. T.W.H. performed: the work on stable p73 knockdown cells; the Fra-1 siRNA experiments; the reporter assay to establish the role of c-JunY170F in the absence of c-Jun; the role of the Pin-1 and CHK2 p73 mutants, and using the junAA cells; and determined the status of phosphorylated c-Jun in p53- and p73-null cells. I.D. was involved in: the quantification of c-Jun phophorylation on p73 induction; the JNK inhibitor experiments; and the generation and characterization of the JNK-null cells in which p73 expression was inducible. W.Q. and N.H.H. performed the ChIP experiments. L.B. performed initial luciferase reporter experiments when attached to the laboratory for a brief period. K.V. provided the SAOS–p73β inducible cells and advised on the initial part of the work. K.S. was responsible for the overall project, in particular, coming up with the ideas and planning the experimental strategies, writing the paper and securing funding for the project.

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Correspondence to Kanaga Sabapathy.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Figures S1, S2, S3, S4 and Supplementary Table S1 (PDF 346 kb)

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Vikhanskaya, F., Toh, W., Dulloo, I. et al. p73 supports cellular growth through c-Jun-dependent AP-1 transactivation. Nat Cell Biol 9, 698–706 (2007). https://doi.org/10.1038/ncb1598

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