Journal
CELL DEATH & DISEASE
Volume 2, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2011.116
Keywords
DPC4/Smad4; colon cancer; PUMA; PAK1
Categories
Funding
- National Research Foundation of Korea
- Ministry of Education, Science and Technology [2010-0022413]
- National Research Foundation of Korea [2010-0022413] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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DPC4 (deleted in pancreatic cancer 4)/Smad4 is an essential factor in transforming growth factor (TGF)-beta signaling and is also known as a frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-beta can contribute to cancer progression through transcriptional target genes, such as Snail, MMPs, and epithelial-mesenchymal transition (EMT)-related genes, loss of Smad4 in human cancer would be required for obtaining the TGF-beta signaling-independent advantage, which should be essential for cancer cell survival. Here, we provide the evidences about novel role of Smad4, serum-deprivation-induced apoptosis. Elimination of serum can obviously increase the Smad4 expression and induces the cell death by p53-independent PUMA induction. Instead, Smad4-deficient cells show the resistance to serum starvation. Induced Smad4 suppresses the PAK1, which promotes the PUMA destabilization. We also found that Siah-1 and pVHL are involved in PAK1 destabilization and PUMA stabilization. In fact, Smad4-expressed cancer tissues not only show the elevated expression of PAK1, but also support our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression. Our results strongly suggest that loss of Smad4 renders the resistance to serum-deprivation-induced cell death, which is the TGF-beta-independent tumor suppressive role of Smad4. Cell Death and Disease (2011) 2, e235; doi:10.1038/cddis.2011.116; published online 1 December 2011
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