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Apaf-1 is a transcriptional target for E2F and p53

Nature Cell Biology 3, 552–558 (2001) | Download Citation

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Abstract

Loss of function of the retinoblastoma protein, pRB, leads to lack of differentiation, hyperproliferation and apoptosis. Inactivation of pRB results in deregulated E2F activity, which in turn induces entry to S-phase and apoptosis. Induction of apoptosis by either the loss of pRB or the deregulation of E2F activity occurs via both p53-dependent and p53-independent mechanisms. The mechanism by which E2F induces apoptosis is still unclear. Here we show that E2F1 directly regulates the expression of Apaf-1, the gene for apoptosis protease-activating factor 1. These results provide a direct link between the deregulation of the pRB pathway and apoptosis. Furthermore, because the pRB pathway is functionally inactivated in most cancers, the identification of Apaf-1 as a transcriptional target for E2F might explain the increased sensitivity of tumour cells to chemotherapy. We also show that, independently of the pRB pathway, Apaf-1 is a direct transcriptional target of p53, suggesting that p53 might sensitize cells to apoptosis by increasing Apaf-1 levels.

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Acknowledgements

We wish to dedicate this work to the memory of M.C.M.'s late husband Pierluigi Molinari. We thank E. Prosperini for technical assistance, T. Jacks for the Rb+/− mice, Y. Lazebnik and D. Huang for anti-Apaf-1 antibodies, K. Vousden for p53 expression constructs and RKO cells, J. R. Nevins for the cyclin E1 reporter construct, A. Bulfone and C. Gattuso for suggestions concerning in situ hybridization, E. Grassilli for discussions and A. Fattaey for discussions and for critical reading of the manuscript. This work was supported by grants from AIRC, FIRC, CNR, The Italian Health Ministery, AICR and the EU's TMR programme.

Author information

    • Francesco Cecconi

    Present address: Department of Biology, Università degli studi 'Tor Vergata', 00133 Roma, Italy

    • Heiko Müller

    Present address: Pharmacia Corporation, Nerviano, Italy

    • M. Cristina Moroni
    •  & Emma S. Hickman

    These authors contributed equally to this work

Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy

    • M. Cristina Moroni
    • , Emma S. Hickman
    • , Eros Lazzerini Denchi
    • , Greta Caprara
    • , Elena Colli
    • , Heiko Müller
    •  & Kristian Helin

  2. Department of Molecular Cell Biology, Max-Planck-Institute of Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany

    • Francesco Cecconi

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Corresponding author

Correspondence to Kristian Helin.

Supplementary information

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  1. 1.

    Figure S1 Sequence of the human APAF-1 promoter. The nucleotide sequence from -871 to +208 bp is shown.

    Figure S2  Release of cytochrome c after activation of ERE2F1 with OHT, in primary wild-type or Apaf-1-/- MEFs.

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DOI

https://doi.org/10.1038/35078527

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