title: Profilin 1 potentiates apoptosis induced by staurosporine in cancer cells.
abstract: The correlation between the loss of Profilin 1 (Pfn1) with tumor progression indicated that Pfn1 is a tumor suppressor in human carcinoma. The molecular mechanisms underlying Pfn1 tumor suppression has yet to be elucidated. In this study, we showed that Pfn1 overexpression sensitizes cancer cells to apoptosis through the typical intrinsic apoptotic pathway. Mechanistically, the increased Pfn1 expression mediated the upregulation of p53R273H, one of the most common tumor-associated hotspot mutations of p53, with transactivation deletion in tumorigenesis and increased localization of p53R273H in cytoplasm. Further studies showed that mutant p53R273H was involved in apoptosis induced by Staurosporine (STS) via transcription-independent mitochondrial functions. We observed (i) the increased cytosolic localization of p53R273H, (ii) the activation of phosphorylation at Ser15, (iii) its mitochondrial localization; Pfn1 acted as a positive regulator of these processes. We also found that Pfn1 interacted with p53R273H and thus facilitated its exertion over the transcription-independent activity in the cytoplasm during drug action. Our results define a new function and mechanism of Pfn1 demonstrating that the combined effect with apoptotic agents led to a synergistic increase in apoptosis. In addition, p53R273H abrogating DNA binding was found to play a major role in the Pfn1- sensitized apoptosis through a transactivation-independent and cytosolic activity.
authors: Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R. China.
authors: W
authors: W
authors: Yao
authors: X
authors: X
authors: Cai
authors: C
authors: C
authors: Liu
authors: Y
authors: Y
authors: Qin
authors: H
authors: H
authors: Cheng
authors: S
authors: S
authors: Ji
authors: W
authors: W
authors: Xu
authors: C
authors: C
authors: Wu
authors: T
authors: T
authors: Chen
authors: J
authors: J
authors: Xu
authors: J
authors: J
authors: Long
authors: Z
authors: Z
authors: Fang
authors: B
authors: B
authors: Qu
authors: M
authors: M
authors: Hoth
authors: Q
authors: Q
authors: Ni
authors: X
authors: X
authors: Zha
authors: X
authors: X
authors: Yu
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms; D010766:Phosphorylation; D051304:Profilins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D019311:Staurosporine / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C495738:PFN1 protein, human; D051304:Profilins; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D019311:Staurosporine