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Kimberly Maxfield, Jennifer Macion, Hariprasad Vankayalapati, Angelique W Whitehurst
Triple negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery and radiation. To identify new intervention targets in TNBC, we used large-scale, loss of function screening to identify molecular vulnerabilities among different oncogenomic backgrounds...
October 3, 2016: Molecular and Cellular Biology
Jinhua Zhou, Albandri Alfraidi, Shu Zhang, Janice Santiago-O'Farrill, Venkata Yerramreddy, Abdulkhaliq Alsaadid, Ahmed Ashour Ahmed, Hailing Yang, Jinsong Liu, Weiqun Mao, Hiroshi Takemori, Yan Wang, Hariprasad Vankayalapati, Zhen Lu, Robert C Bast
PURPOSE: SIK2 is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy. Here we examine the effects of a novel small molecule SIK2 inhibitor, ARN-3236, on sensitivity to paclitaxel in ovarian cancer. EXPERIMENTAL DESIGN: SIK2 expression was determined in ovarian cancer tissue samples and cell lines. ARN-3236 was tested for its efficiency to inhibit growth and enhance paclitaxel sensitivity in cultures and xenografts of ovarian cancer cell lines...
September 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jacob A Galan, Joseph Avruch
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45...
October 4, 2016: Biochemistry
(no author information available yet)
A recent study reveals that the kinase SIK2 helps ovarian cancer cells metastasize and establish themselves in the fat-rich tissues of the abdominal cavity by promoting fatty-acid metabolism and cell proliferation. Mice bearing SIK2-overexpressing human ovarian cancer cells had larger, more abundant metastases than those whose tumors bore an inactive form of the kinase.
October 2016: Cancer Discovery
Jinwoo Lee, Takeshi Yamazaki, Hui Dong, Colin Jefcoate
The Steroidogenic acute regulatory protein (StAR) directs mitochondrial cholesterol uptake through a C-terminal cholesterol binding domain (CBD) and a 62 amino acid N-terminal regulatory domain (NTD) that contains an import sequence and conserved sites for inner membrane metalloproteases. Deletion of the NTD prevents mitochondrial import while maintaining steroidogenesis but with compromised cholesterol homeostasis. The rapid StAR-mediated cholesterol transfer in adrenal cells depends on concerted mRNA translation, p37 StAR phosphorylation and controlled NTD cleavage...
August 10, 2016: Molecular and Cellular Endocrinology
Fabrizio Miranda, David Mannion, Shujuan Liu, Yiyan Zheng, Lingegowda S Mangala, Clara Redondo, Sandra Herrero-Gonzalez, Ruoyan Xu, Charlotte Taylor, Donatien Fotso Chedom, Mohammad Karaminejadranjbar, Ashwag Albukhari, Dahai Jiang, Sunila Pradeep, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Eidarus Salah, Kamal R Abdul Azeez, Jonathan M Elkins, Leticia Campo, Kevin A Myers, Daniel Klotz, Serena Bivona, Sunanda Dhar, Robert C Bast, Hideyuki Saya, Hwan Geun Choi, Nathanael S Gray, Roman Fischer, Benedikt M Kessler, Christopher Yau, Anil K Sood, Takeshi Motohara, Stefan Knapp, Ahmed Ashour Ahmed
The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2...
August 8, 2016: Cancer Cell
H-H Wang, C-Y Lin, S-H Su, C-T Chuang, Y-L Chang, T-Y Lee, S-C Lee, C-J Chang
Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability...
2016: Cell Death & Disease
Yingyi Liu, Sujie Gao, Xuebo Chen, Meihan Liu, Cuiying Mao, Xuedong Fang
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts...
May 28, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Thomas B Sundberg, Yanke Liang, Huixian Wu, Hwan Geun Choi, Nam Doo Kim, Taebo Sim, Liv Johannessen, Adam Petrone, Bernard Khor, Daniel B Graham, Isabel J Latorre, Andrew J Phillips, Stuart L Schreiber, Jose Perez, Alykhan F Shamji, Nathanael S Gray, Ramnik J Xavier
Salt-inducible kinases (SIKs) are promising therapeutic targets for modulating cytokine responses during innate immune activation. The study of SIK inhibition in animal models of disease has been limited by the lack of selective small-molecule probes suitable for modulating SIK function in vivo. We used the pan-SIK inhibitor HG-9-91-01 as a starting point to develop improved analogs, yielding a novel probe 5 (YKL-05-099) that displays increased selectivity for SIKs versus other kinases and enhanced pharmacokinetic properties...
August 19, 2016: ACS Chemical Biology
Zhen-Ning Zhang, Lulu Gong, Sihan Lv, Jian Li, Xiaolu Tai, Wenqi Cao, Bing Peng, Shen Qu, Weida Li, Chao Zhang, Bing Luan
Fatty acid oxidation and subsequent ketogenesis is one of the major mechanisms to maintain hepatic lipid homeostasis under fasting conditions. Fasting hormone glucagon has been shown to stimulate ketone body production through activation of PPARα; however, the signal pathway linking glucagon to PPARα is largely undiscovered. Here we report that a SIK2-p300-PPARα cascade mediates glucagon's effect on ketogenesis. p300 interacts with PPARα through a conserved LXXLL motif and enhances its transcriptional activity...
2016: Scientific Reports
Wen-Qi Du, Jun-Nian Zheng, Dong-Sheng Pei
INTRODUCTION: The salt-inducible kinases originally cloned in adrenal glands of high salt diet-fed rats, generally named as SIKs, are highly evolutionarily conserved serine/threonine protein kinases belonging to a family of AMP-activated protein kinase (AMPK). Overexpression of SIK2 and SIK3 is discovered in many tumors. Whereas, SIK1 expression was significantly lower in tumors than in normal tissues. AREAS COVERED: The main aim of our review is to introduce the signaling pathways as well as its mechanisms underlying their activity regulation, and especially the roles they play in cancer, which may shed light on the prospects of the cancer prevention and therapeutic targeting of SIKs in the future...
2016: Expert Opinion on Therapeutic Targets
David Curtis
For biological and statistical reasons it makes sense to combine information from variants at the level of the gene. One may wish to give more weight to variants which are rare and those that are more likely to affect function. A combined weighting scheme, implemented in the SCOREASSOC program, was applied to whole exome sequence data for 1392 subjects with schizophrenia and 982 with obesity from the UK10K project. Results conformed fairly well with null hypothesis expectations and no individual gene was strongly implicated...
January 2016: Annals of Human Genetics
Yumi Itoh, Masato Sanosaka, Hiroyuki Fuchino, Yasuhito Yahara, Ayako Kumagai, Daisaku Takemoto, Mai Kagawa, Junko Doi, Miho Ohta, Noriyuki Tsumaki, Nobuo Kawahara, Hiroshi Takemori
Salt-inducible kinases (SIKs), members of the 5'-AMP-activated protein kinase (AMPK) family, are proposed to be important suppressors of gluconeogenic programs in the liver via the phosphorylation-dependent inactivation of the CREB-specific coactivator CRTC2. Although a dramatic phenotype for glucose metabolism has been found in SIK3-KO mice, additional complex phenotypes, dysregulation of bile acids, cholesterol, and fat homeostasis can render it difficult to discuss the hepatic functions of SIK3. The aim of this study was to examine the cell autonomous actions of SIK3 in hepatocytes...
July 17, 2015: Journal of Biological Chemistry
Ya-Nan Li, Yi-Qun Cao, Xi Wu, Guo-Sheng Han, Lai-Xing Wang, Yu-Hui Zhang, Xin Chen, Bin Hao, Zhi-Jian Yue, Jian-Min Liu
BACKGROUND: PPP2R2C encodes a gamma isoform of the regulatory subunit B55 subfamily consisting PP2A heterotrimeric with A and C subunits. Currently, the precise functions of B55gamma in cancer are still under investigating. In this project, we reported a novel function of B55gamma in the regulation of glucose metabolism in Glioma cells. METHODS: Western blot and immunoprecipitation were performed to determine protein expression and interaction. Cell viability was measured by Typan Blue staining and direct cell counting using hematocytometer...
2015: Cancer Cell International
Masato Sanosaka, Minoru Fujimoto, Tomoharu Ohkawara, Takahiro Nagatake, Yumi Itoh, Mai Kagawa, Ayako Kumagai, Hiroyuki Fuchino, Jun Kunisawa, Tetsuji Naka, Hiroshi Takemori
Macrophages play important roles in the innate immune system during infection and systemic inflammation. When bacterial lipopolysaccharide (LPS) binds to Toll-like receptor 4 on macrophages, several signalling cascades co-operatively up-regulate gene expression of inflammatory molecules. The present study aimed to examine whether salt-inducible kinase [SIK, a member of the AMP-activated protein kinase (AMPK) family] could contribute to the regulation of immune signal not only in cultured macrophages, but also in vivo...
June 2015: Immunology
Hélène Bon, Karan Wadhwa, Alexander Schreiner, Michelle Osborne, Thomas Carroll, Antonio Ramos-Montoya, Helen Ross-Adams, Matthieu Visser, Ralf Hoffmann, Ahmed Ashour Ahmed, David E Neal, Ian G Mills
UNLABELLED: Salt-inducible kinase 2 (SIK2) is a multifunctional kinase of the AMPK family that plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell-cycle progression and a negative regulator of CREB1 activity...
April 2015: Molecular Cancer Research: MCR
Emma Henriksson, Johanna Säll, Amélie Gormand, Sebastian Wasserstrom, Nicholas A Morrice, Andreas M Fritzen, Marc Foretz, David G Campbell, Kei Sakamoto, Mikael Ekelund, Eva Degerman, Karin G Stenkula, Olga Göransson
Salt-inducible kinase 2 (SIK2) is an AMP-activated protein kinase (AMPK) related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-mediated phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2), CRTC3 and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type but not Ser358Ala SIK2, was reduced by cAMP elevation...
February 1, 2015: Journal of Cell Science
James Ozanne, Alan R Prescott, Kristopher Clark
Macrophages switch to an anti-inflammatory, 'regulatory'-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of 'regulatory'-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of 'regulatory'-like macrophages...
January 15, 2015: Biochemical Journal
Kashyap Patel, Marc Foretz, Allison Marion, David G Campbell, Robert Gourlay, Nadia Boudaba, Emilie Tournier, Paul Titchenell, Mark Peggie, Maria Deak, Min Wan, Klaus H Kaestner, Olga Göransson, Benoit Viollet, Nathanael S Gray, Morris J Birnbaum, Calum Sutherland, Kei Sakamoto
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated...
2014: Nature Communications
Yvan Wenger, Wanda Buzgariu, Silke Reiter, Brigitte Galliot
The impact of injury-induced immune responses on animal regenerative processes is highly variable, positive or negative depending on the context. This likely reflects the complexity of the innate immune system that behaves as a sentinel in the transition from injury to regeneration. Early-branching invertebrates with high regenerative potential as Hydra provide a unique framework to dissect how injury-induced immune responses impact regeneration. A series of early cellular events likely require an efficient immune response after amputation, as antimicrobial defence, epithelial cell stretching for wound closure, migration of interstitial progenitors toward the wound, cell death, phagocytosis of cell debris, or reconstruction of the extracellular matrix...
August 2014: Seminars in Immunology
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