title: Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway.
abstract: 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.
authors: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors: S-H
authors: SH
authors: Lee
authors: Y-S
authors: YS
authors: Jung
authors: J-Y
authors: JY
authors: Chung
authors: A Y
authors: AY
authors: Oh
authors: S-J
authors: SJ
authors: Lee
authors: D H
authors: DH
authors: Choi
authors: S M
authors: SM
authors: Jang
authors: K-S
authors: KS
authors: Jang
authors: S S
authors: SS
authors: Paik
authors: N-C
authors: NC
authors: Ha
authors: B-J
authors: BJ
authors: Park
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D015820:Cadherins; D016895:Culture Media, Serum-Free; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D054462:p21-Activated Kinases