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Joelle N Zambrano, Christina J Williams, Carly Bess Williams, Lonzie Hedgepeth, Pieter Burger, Tinslee Dilday, Scott T Eblen, Kent Armeson, Elizabeth G Hill, Elizabeth S Yeh
HUNK is a protein kinase that is implicated in HER2-positive (HER2+) breast cancer progression and resistance to HER2 inhibitors. Though prior studies suggest there is therapeutic potential for targeting HUNK in HER2+ breast cancer, pharmacological agents that target HUNK are yet to be identified. A recent study showed that the broad-spectrum kinase inhibitor staurosporine binds to the HUNK catalytic domain, but the effect of staurosporine on HUNK enzymatic activity was not tested. We now show that staurosporine inhibits the kinase activity of a full length HUNK protein...
November 13, 2018: Oncotarget
Andrew F Roberts, Elizabeth C Hunke, Richard Allard, David A Bailey, Anthony P Craig, Jean-François Lemieux, Matthew D Turner
A new collaborative organization for sea-ice model development, the CICE Consortium, has devised quality control procedures to maintain the integrity of its numerical codes' physical representations, enabling broad participation from the scientific community in the Consortium's open software development environment. Using output from five coupled and uncoupled configurations of the Los Alamos Sea Ice Model, CICE, we formulate quality control methods that exploit common statistical properties of sea-ice thickness, and test for significant changes in model results in a computationally efficient manner...
September 28, 2018: Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences
Megan Hunke, Wuilian Martinez, Akshay Kashyap, Treyvon Bokoskie, Mahesh Pattabiraman, Surabhi Chandra
BACKGROUND/AIM: Breast cancer is the second leading cause of cancer-related deaths in US, which necessitates constant research for medications with minimal adverse effects. The aim of the study was to determine if certain cinnamic acid dimers (CADs) exhibit higher cytotoxicity in breast cancer cells than against non-tumorigenic cells. MATERIALS AND METHODS: These dimers have not been explored, so far, due to their complex stereochemistry; cavitand-mediated photodimerization (CMP) method was used to produce several CADs, which were tested for cytotoxicity, apoptosis and cell cycle inhibition...
August 2018: Anticancer Research
Alaini Priebe, Megan Hunke, Raquel Tonello, Yogesh Sonawane, Temugin Berta, Amarnath Natarajan, Nattamai Bhuvanesh, Mahesh Pattabiraman, Surabhi Chandra
Purpose: Search for alternate pain medications has gained more importance in the past few years due to adverse effects associated with currently prescribed drugs including nervous system dysfunction with opioids, gastrointestinal discomfort with nonsteroidal anti-inflammatory drugs, and cardiovascular anomalies with cyclooxygenase-2 (COX-2) inhibitors. Phytomedicine has been explored for the treatment of pain, as these have been used for generations in regional communities and tend to lack major side effects in general...
2018: Journal of Pain Research
Valérie Bernard, Chiara Villa, Aurélie Auguste, Sophie Lamothe, Anne Guillou, Agnès Martin, Sandrine Caburet, Jacques Young, Reiner A Veitia, Nadine Binart
Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient ( Prlr -/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr -/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development...
January 19, 2018: Oncotarget
Emina Ćudić, Kristin Surmann, Gianna Panasia, Elke Hammer, Sabine Hunke
BACKGROUND: The aminoglycoside antibiotic gentamicin was supposed to induce a crosstalk between the Cpx- and the Arc-two-component systems (TCS). Here, we investigated the physical interaction of the respective TCS components and compared the results with their respective gene expression and protein abundance. The findings were interpreted in relation to the global proteome profile upon gentamicin treatment. RESULTS: We observed specific interaction between CpxA and ArcA upon treatment with the aminoglycoside gentamicin using Membrane-Strep-tagged protein interaction experiments (mSPINE)...
September 18, 2017: BMC Microbiology
Joelle N Zambrano, Benjamin A Neely, Elizabeth S Yeh
Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2+ /ErbB2+ ) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date...
May 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Kendall Phelps-Polirer, Melissa A Abt, Danzell Smith, Elizabeth S Yeh
Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance...
2016: PloS One
Kristin Surmann, Emina Ćudić, Elke Hammer, Sabine Hunke
Two-component systems (TCS) play a pivotal role for bacteria in stress regulation and adaptation. However, it is not well understood how these systems are modulated to meet bacterial demands. Especially, for those TCS using an accessory protein to integrate additional signals, no data concerning the role of the accessory proteins within the coordination of the response is available. The Cpx envelope stress two-component system, composed of the sensor kinase CpxA and the response regulator CpxR, is orchestrated by the periplasmic protein CpxP which detects misfolded envelope proteins and inhibits the Cpx system in unstressed cells...
August 2016: MicrobiologyOpen
Patrick Hörnschemeyer, Viktoria Liss, Ralf Heermann, Kirsten Jung, Sabine Hunke
Two-component systems are the major means by which bacteria couple adaptation to environmental changes. All utilize a phosphorylation cascade from a histidine kinase to a response regulator, and some also employ an accessory protein. The system-wide signaling fidelity of two-component systems is based on preferential binding between the signaling proteins. However, information on the interaction kinetics between membrane embedded histidine kinase and its partner proteins is lacking. Here, we report the first analysis of the interactions between the full-length membrane-bound histidine kinase CpxA, which was reconstituted in nanodiscs, and its cognate response regulator CpxR and accessory protein CpxP...
2016: PloS One
Diederik P C de Rooy, Roula Tsonaka, Maria L E Andersson, Kristina Forslind, Alexandra Zhernakova, Mojca Frank-Bertoncelj, Caroline G F de Kovel, Bobby P C Koeleman, Désirée M F M van der Heijde, Tom W J Huizinga, René E M Toes, Jeanine J Houwing-Duistermaat, Caroline Ospelt, Björn Svensson, Annette H M van der Helm-van Mil
OBJECTIVE: Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients. METHODS: A genome-wide association study was done with 262 ACPA-negative patients with early RA included in the Leiden Early Arthritis Clinic and related to radiographic joint destruction over 7 years...
August 2015: Journal of Rheumatology
Rebecca Keller, Candan Ariöz, Nicole Hansmeier, Filippa Stenberg-Bruzell, Malin Burstedt, David Vikström, Amelie Kelly, Åke Wieslander, Daniel O Daley, Sabine Hunke
The Cpx stress response system is induced by various environmental and cellular stimuli. It is also activated in Escherichia coli strains lacking the major phospholipid, phosphatidylethanolamine (PE). However, it is not known whether CpxA directly senses changes in the lipid bilayer or the presence of misfolded proteins due to the lack of PE in their membranes. To address this question, we used an in vitro reconstitution system and vesicles with different lipid compositions to track modulations in the activity of CpxA in different lipid bilayers...
June 16, 2015: Biochemistry
Karen R Reed, Igor V Korobko, Natalia Ninkina, Elena V Korobko, Ben R Hopkins, James L Platt, Vladimir Buchman, Alan R Clarke
BACKGROUND: Conditional deletion of the tumour suppressor gene Apc within the murine intestine results in acute Wnt signalling activation. The associated over-expression of a myriad of Wnt signalling target genes yields phenotypic alterations that encompass many of the hallmarks of neoplasia. Previous transcriptomic analysis aimed at identifying genes that potentially play an important role in this process, inferred the Hormonally upregulated Neu-associated kinase (HUNK/Mak-v/Bstk1) gene as a possible candidate...
2015: BMC Cancer
Karen R Reed, Igor V Korobko, Natalia Ninkina, Elena V Korobko, Ben R Hopkins, James L Platt, Vladimir Buchman, Alan R Clarke
BACKGROUND: Conditional deletion of the tumour suppressor gene Apc within the murine intestine results in acute Wnt signalling activation. The associated over-expression of a myriad of Wnt signalling target genes yields phenotypic alterations that encompass many of the hallmarks of neoplasia. Previous transcriptomic analysis aimed at identifying genes that potentially play an important role in this process, inferred the Hormonally upregulated Neu-associated kinase (HUNK/Mak-v/Bstk1) gene as a possible candidate...
2015: BMC Cancer
Elizabeth S Yeh, Melissa A Abt, Elizabeth G Hill
Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment failure. Several recent studies indicate that activation of autophagy contributes to trastuzumab and lapatinib resistance and demonstrate that impairing autophagy in breast cancer cells is therapeutically beneficial...
January 2015: Breast Cancer Research and Treatment
Lei Wei, Ping Jiang, Malathy Sony Subramanian Manimekalai, Cornelia Hunke, Gerhard Grüber, Konstantin Pervushin, Yuguang Mu
The process of islet amyloid polypeptide (IAPP) formation and the prefibrillar oligomers are supposed to be one of the pathogenic agents causing pancreatic β-cell dysfunction. The human IAPP (hIAPP) aggregates easily and therefore, it is difficult to characterize its structural features by standard biophysical tools. The rat version of IAPP (rIAPP) that differs by six amino acids when compared with hIAPP, is not prone to aggregation and does not form amyloid fibrils. Similar to hIAPP it also demonstrates random-coiled nature in solution...
2015: Advances in Experimental Medicine and Biology
Karolin Tschauner, Patrick Hörnschemeyer, Volker Steffen Müller, Sabine Hunke
Two-component systems, consisting of an inner membrane sensor kinase and a cytosolic response regulator, allow bacteria to respond to changes in the environment. Some two-component systems are additionally orchestrated by an accessory protein that integrates additional signals. It is assumed that spatial and temporal interaction between an accessory protein and a sensor kinase modifies the activity of a two-component system. However, for most accessory proteins located in the bacterial envelope the mechanistic details remain unclear...
2014: PloS One
Sabrina Graf, Dominik Schmieden, Karolin Tschauner, Sabine Hunke, Gottfried Unden
The DctSR two-component system of Bacillus subtilis controls the expression of the aerobic C4-dicarboxylate transporter DctA. Deletion of DctA leads to an increased dctA expression. The inactivation of DctB, an extracellular binding protein, is known to inhibit the expression of dctA. Here, interaction between the sensor kinase DctS and the transporter DctA as well as the binding protein DctB was demonstrated in vivo using streptavidin (Strep) or His protein interaction experiments (mSPINE or mHPINE), and the data suggest that DctA and DctB act as cosensors for DctS...
March 2014: Journal of Bacteriology
Volker Steffen Müller, Karolin Tschauner, Sabine Hunke
UNLABELLED: Membrane proteins are essential for cell viability and are therefore important therapeutic targets(1-3). Since they function in complexes(4), methods to identify and characterize their interactions are necessary(5). To this end, we developed the Membrane Strep-protein interaction experiment, called Membrane-SPINE(6). This technique combines in vivo cross-linking using the reversible cross-linker formaldehyde with affinity purification of a Strep-tagged membrane bait protein...
2013: Journal of Visualized Experiments: JoVE
Elizabeth S Yeh, George K Belka, Ann E Vernon, Chien-Chung Chen, Jason J Jung, Lewis A Chodosh
The protooncogenes Akt and c-myc each positively regulate cell growth and proliferation, but have opposing effects on cell survival. These oncogenes cooperate to promote tumorigenesis, in part because the prosurvival effects of Akt offset the proapoptotic effects of c-myc. Akt's ability to counterbalance c-myc's proapoptotic effects has primarily been attributed to Akt-induced stimulation of prosurvival pathways that indirectly antagonize the effects of c-myc. We report a more direct mechanism by which Akt modulates the proapoptotic effects of c-myc...
April 9, 2013: Proceedings of the National Academy of Sciences of the United States of America
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