Sung-Hee Kim

The Hippo pathway plays crucial roles in regulating organ size and stem cell homeostasis. Although the signalling cascade of the core Hippo kinases is relatively well understood, little is known about the mechanisms that modulate the activity of the Hippo pathway. Here, we report identification of NEDD4, a HECT-type E3 ubiquitin ligase, as a regulatory component of the Hippo pathway. We demonstrate that NEDD4 ubiquitylates and destabilizes WW45 and LATS kinase, both of which are required for active Hippo signalling. Interestingly, MST1 protects WW45, but not LATS2, against NEDD4. We also provide evidence indicating that NEDD4 inactivation at high cell density is a prerequisite for the elevated Hippo activity linked to contact inhibition. Moreover, NEDD4 promotes intestinal stem cell renewal in Drosophila by suppressing Hippo signalling. Collectively, we present a regulatory mechanism by which NEDD4 controls the Hippo pathway leading to coordinated cell proliferation and apoptosis. The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.

// Sung-Hee Kim 1 , Soon-Chan Kim 2 and Ja-Lok Ku 1, 2 1 Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea 2 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea Correspondence to: Ja-Lok Ku, email: kujalok@snu.ac.kr Keywords: colorectal cancer, 5-Fu resistant-cell line, metformin, cancer stem cell (CSC), DNA replication Received: January 17, 2017      Accepted: April 27, 2017      Published: May 11, 2017 ABSTRACT Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR). Moreover, a treatment that combines 5-Fu and metformin was found to have a synergistic effect on the cell proliferation rate, especially in SNU-C5_5FuR, which was mediated by the activation of AMPK pathway and NF-ƙB pathway, well-known metformin mechanisms. In this study, we suggested novel anticancer mechanism of metformin that inhibited DNA replication machinery, such as the MCM family in SNU-C5_5FuR. In conclusion, we provided that how metformin acts as not only a chemo-sensitizer, but also as a synergistic effector of 5-Fu in the 5-Fu resistant-cell line. We speculate that metformin used for adjuvant therapy is effective on 5-Fu resistant cancer cells.

BACKGROUND AND PURPOSE: This study aimed to determine the patterns and etiologies of acquired ocular motor nerve palsy (OMNP) diagnosed in neurology clinics. We also investigated the clinical features that may predict the causes other than microvascular ischemia in isolated OMNP. METHODS: =47) groups. We investigated the underlying etiologies of acquired OMNP. We also estimated the frequency of microvascular ischemia and other causes in isolated OMNP, and sought to determine the clinical features that can predict the causes other than microvascular ischemia. RESULTS: <0.001). The intensity of headache was the only risk factor for causes other than microvascular ischemia in isolated OMNP. CONCLUSIONS: Vascular and inflammatory disorders are the most common causes of acquired OMNP diagnosed in neurology clinics. Microvascular ischemia was the predominant cause of isolated OMNP. Severe headache indicates causes other than microvascular ischemia in isolated OMNP.