We have previously demonstrated that 40%-70% of elf ؉/؊ mice spontaneously develop hepatocellular cancer (HCC) within 15 months, revealing the importance of the transforming growth factor-beta (TGF-) signaling pathway in suppressing tumorigenesis in the liver. The current study was carried out to investigate mechanisms by which embryonic liver fodrin ( Abbreviations: ␣-SMA, alpha-smooth muscle actin; BrdU, bromodeoxyuridine; CPAE, cow pulmonary artery endothelial; ELF, embryonic liver fodrin; FBHE, fetal bovine heart endothelial; ⌯CC, hepatocellular cancer;
Transforming growth factor beta (TGF-b) is an important regulator of cell growth, and loss of TGF-b signaling is a hallmark of carcinogenesis. The Smad3/4 adaptor protein b2-spectrin (b2SP) is emerging as a potent regulator of tumorigenesis through its ability to modulate the tumor suppressor function of TGF-b. However, to date the role of the TGFb signaling pathway at specific stages of the development of hepatocellular carcinoma (HCC), particularly in relation to the activation of other oncogenic pathways, remains poorly delineated. Here we identify a mechanism by which b2SP, a crucial Smad3 adaptor, modulates cyclin dependent kinase 4 (CDK4), cell cycle progression, and suppression of HCC. Increased expression of b2SP inhibits phosphorylation of the retinoblastoma gene product (Rb) and markedly reduces CDK4 expression to a far greater extent than other CDKs and cyclins. Furthermore, suppression of CDK4 by b2SP efficiently restores Rb hypophosphorylation and cell cycle arrest in G 1 . We further demonstrate that b2SP interacts with CDK4 and Smad3 in a competitive and TGF-b-dependent manner. In addition, haploinsufficiency of cdk4 in b2sp 1/2 mice results in a dramatic decline in HCC formation compared to that observed in b2sp 1/2 mice. Conclusion: b2SP deficiency leads to CDK4 activation and contributes to dysregulation of the cell cycle, cellular proliferation, oncogene overexpression, and the formation of HCCs. Our data highlight CDK4 as an attractive target for the pharmacologic inhibition of HCC and demonstrate the importance of b2sp 1/2 mice as a model of preclinical efficacy in the treatment of HCC. (HEPATOLOGY 2011;53:1676-1684 T he transforming growth factor b (TGF-b) signaling pathway is involved in multiple cellular processes, including cell growth, differentiation, adhesion, migration, and apoptosis. TGF-b is particularly active as an antimitogenic cytokine, functioning as a profound tumor suppressor by inhibiting cell cycle progression and arresting cells in early G 1 phase. TGFb signaling is mediated by type I and type II transmembrane serine/threonine kinase receptors (TbRI and TbRII) and such intracellular mediators as the Abbreviations: b2SP, b2-spectrin; CDK4, cyclin dependent kinase 4; HCC, hepatocellular cancer; TGF-b, transforming growth factor-b. From the
These data suggest that β2-spectrin deficiency leads to inactivation of TGF-β/Smad signalling and contributes to dysregulation of the cell cycle, proliferation, differentiation, and the cytoskeletal network, and it leads to defective heart development. Our data demonstrate that β2-spectrin is required for proper development of the heart and that disruption of β2-spectrin is a potential underlying cause of congenital heart defects.
We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-β signaling through Smad3 and Smad4 localization. Notably elf +/− /smad4 +/− mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf −/− cells and elf +/− / smad4 +/− mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf −/− MEFs show a disruption of G 1 /S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G 1 /S checkpoint and senescence contribute their increment of susceptibility to malignant transformation. KeywordsELF; Gastric cancer; Smad4; Cell cycle; Senescence Gastric carcinoma is a leading cause of cancer-related deaths worldwide. With approximately 755,000 new cases diagnosed each year, it ranks second in incidence only to lung cancer. Most gastric cancers are diagnosed at an advanced stage, contributing to a dismal 5-year survival rate of under 20% [1][2][3]. The factors that govern progression from gastric epithelial cell hyperplasia through dysplasia to in situ carcinoma and invasive disease remain poorly understood and are thought to involve multiple pathways.Helicobacter pylori is one of the most prominent reasons in gastric oncogenic activation by the cytotoxic-associated antigen A (cag A), which is known to bind signaling molecules such as erb2, c-met, and zo-1. Infection with H. pylori perturbs several signaling pathways
The ubiquitously expressed β2-spectrin (β2SP, SPTBN1) is the most common non-erythrocytic member of the β-spectrin gene family. Loss of β2-spectrin leads to defects in liver development, and its haploinsufficiency spontaneously leads to chronic liver disease and the eventual development of hepatocellular cancer. However, the specific role of β2-spectrin in liver homeostasis remains to be elucidated. Here, we reported that β2-spectrin was cleaved by caspase-3/7 upon treatment with acetaminophen which is the main cause of acute liver injury. Blockage of β2-spectrin cleavage robustly attenuated β2-spectrin-specific functions, including regulation of the cell cycle, apoptosis, and transcription. Cleaved fragments of β2-spectrin were physiologically active, and the N- and C-terminal fragments retained discrete interaction partners and activity in transcriptional regulation and apoptosis, respectively. Cleavage of β2-spectrin facilitated the redistribution of the resulting fragments under conditions of liver damage induced by acetaminophen. In contrast, downregulation of β2-spectrin led to resistance to acetaminophen-induced cytotoxicity, and its insufficiency in the liver promoted suppression of acetaminophen-induced liver damage and enhancement of liver regeneration. Conclusions: β2-Spectrin, a TGF-β mediator and signaling molecule, is cleaved and activated by caspase-3/7, consequently enhancing apoptosis and transcriptional control to determine cell fate upon liver damage. These findings have extended our knowledge on the spectrum of β2-spectrin functions from a scaffolding protein to a target and transmitter of TGF-β in liver damage.
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