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Molecular and Cellular Biology, June 2007, p. 3920-3935, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01219-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Upregulation of Twist-1 by NF-B Blocks Cytotoxicity Induced by Chemotherapeutic Drugs

Can G. Pham,^1,2 Concetta Bubici,² Francesca Zazzeroni,^2, James R. Knabb,² Salvatore Papa,² Christian Kuntzen,² and Guido Franzoso^2*

Department of Pathology,¹ The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, Illinois 60637²

Received 6 July 2006/ Returned for modification 5 September 2006/ Accepted 19 February 2007

NF-B/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-B blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-B is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-B has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-B inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-B. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-B. Twist-1 is an evolutionarily conserved target of NF-B, blocks PCD induced by chemotherapeutic drugs and TNF- in NF-B-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19^ARF signaling, suggesting that it mediates a novel protective mechanism activated by NF-B. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-B-dependent chemoresistance.

Published ahead of print on 2 April 2007.

Present address: Department of Experimental Medicine, The University of L'Aquila, Via Vetoio-Coppito 2, 67100 L'Aquila, Italy.

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