Carcinogenesis Advance Access published online on March 28, 2003
Carcinogenesis, doi:10.1093/carcin/bgg032
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Cancer Molecular Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor MI 48109, USA
* Corresponding author. E-mail: yi.sun{at}pfizer.com.
Received 30 May 2002
; revised 2 January 2003
; accepted 21 February 2003
In an effort to search for genes responsible for cell growth arrest and/or apoptosis associated with p53 signaling pathways, we profiled a human lung carcinoma line H1299, expressing a temperature sensitive p53 (V138) against Affymetric human U95Av2 GeneChip A, consisting of 12,000 genes. One hundred thirty-three genes were identified that were either induced or repressed in response to p53-dependent cell growth arrest and apoptotic conditions. Among them, the
AMPK
1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression
2 Cancer Molecular Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
3 Department of Radiation Oncology, University of Michigan, Ann Arbor MI 48109, USA
1 subunit, but not other subunits of the AMP-activated protein kinase (AMPK) was strongly induced. The p53 consensus binding site search in the AMPK-1 promoter and the first intron identified 4 such putative sites. However, p53 failed to bind to any of these sites as assayed by in vitro gel retardation and in vivo chromatin immunoprecipitation. Furthermore, Northern analysis showed that induction of this gene is independent of p53, as increased expression of the gene was observed in p53 null H1299/Neo control cells when the temperature was shifted to 32°C. Moreover, a DNA damaging agent, etoposide, also induced 1 subunit expression in multiple human tumor cells, regardless of p53 status. Thus, the 1 subunit of AMPK is not a p53 down-stream target gene, but can be induced by cold shock or the chemotherapeutic drug, etoposide in a p53 independent manner. To determine the biological significance of AMPK1 induction, we over-expressed the gene in two tumor cell lines, H1299 and U2-OS. In both lines, forced AMPK1 expression inhibits tumor cell growth, suggesting that AMPK1 induction may facilitate stress-induced growth inhibition and cell killing.1 subunit of AMP-activated protein kinase, Cold shock, Etoposide, p53, Tumor growth inhibition
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