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Vol. 16, Issue 2, 943-953, February 2005

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Transcriptional Networks and Cellular Senescence in Human Mammary Fibroblasts

K. Hardy ^*, L. Mansfield ^*, A. Mackay  , S. Benvenuti ^* , S. Ismail ^* ||, P. Arora ^*, M. J. O'Hare , and P. S. Jat ^* ¶ #

^* Ludwig Institute for Cancer Research, University College School of Medicine, London W1W 7BS, United Kingdom; LICR-UCL Breast Cancer Laboratory, Department of Surgery, Royal Free and University College School of Medicine, London W1P 7LD, United Kingdom; and ^¶ Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom

Submitted May 12, 2004; Revised November 18, 2004; Accepted November 19, 2004
Monitoring Editor: Keith Yamamoto

Senescence, the molecular program that limits the finite proliferative potential of a cell, acts as an important barrier to protect the body from cancer. Techniques for measuring transcriptome changes and for modulating their expression suggest that it may be possible to dissect the transcriptional networks underlying complex cellular processes. HMF3A cells are conditionally immortalized human mammary fibroblasts that can be induced to undergo coordinated senescence. Here, we used these cells in conjunction with microarrays, RNA interference, and in silico promoter analysis to promote the dissection of the transcriptional networks responsible for regulating cellular senescence. We first identified changes in the transcriptome when HMF3A cells undergo senescence and then compared them with those observed upon replicative senescence in primary human mammary fibroblasts. In addition to DUSP1 and known p53 and E2F targets, a number of genes such as PHLDA1, NR4A3, and a novel splice variant of STAC were implicated in senescence. Their role in senescence was then analyzed by RNA silencing followed by microarray analysis. In silico promoter analysis of all differential genes predicted that nuclear factor-B and C/EBP transcription factors are activated upon senescence, and we confirmed this by electrophoretic mobility shift assay. The results suggest a putative signaling network for cellular senescence.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present address: Breakthrough Toby Robins Breast Cancer Research Centre, London SW3 6JB, United Kingdom

Present address: University of Torino Medical School, 10060 Candiolo, Italy

^|| Present address: Department of Biochemistry, University of Jordan, Amman 11942, Jordan

^# Corresponding author. E-mail address: parmjit{at}ludwig.ucl.ac.uk.

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