Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway.
Summary of "Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway."
DPC4 (deleted in pancreatic cancer 4)/Smad4 is an essential factor in transforming growth factor (TGF)-β signaling and is also known as a frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-β 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-β 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-β-independent tumor suppressive role of Smad4.
Affiliation
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
Journal Details
This article was published in the following journal.
Name: Cell death & disease
ISSN: 2041-4889
Pages: e235
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22130069
- DOI: http://dx.doi.org/10.1038/cddis.2011.116
Medical and Biotech [MESH] Definitions
Antigens, Viral, Tumor
Those proteins recognized by antibodies from serum of animals bearing tumors induced by viruses; these proteins are presumably coded for by the nucleic acids of the same viruses that caused the neoplastic transformation.
Smad4 Protein
A signal transducing adaptor protein and tumor suppressor protein. It forms a complex with activated RECEPTOR-REGULATED SMAD PROTEINS. The complex then translocates to the CELL NUCLEUS and regulates GENETIC TRANSCRIPTION of target GENES.
Tumor Necrosis Factor-alpha
Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.
Antigens, Tumor-associated, Carbohydrate
Carbohydrate antigens expressed by malignant tissue. They are useful as tumor markers and are measured in the serum by means of a radioimmunoassay employing monoclonal antibodies.
Inappropriate Adh Syndrome
A condition of HYPONATREMIA and renal salt loss attributed to overexpansion of BODY FLUIDS resulting from sustained release of ANTIDIURETIC HORMONES which stimulates renal resorption of water. It is characterized by normal KIDNEY function, high urine OSMOLALITY, low serum osmolality, and neurological dysfunction. Etiologies include ADH-producing neoplasms, injuries or diseases involving the HYPOTHALAMUS, the PITUITARY GLAND, and the LUNG. This syndrome can also be drug-induced.
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