@article{MTMT:3354869, title = {PI3K/Akt Cooperates with Oncogenic Notch by Inducing Nitric Oxide-Dependent Inflammation}, url = {https://m2.mtmt.hu/api/publication/3354869}, author = {Villegas, SN and Gombos, Rita I and Garcia-Lopez, L and Gutierrez-Perez, I and Garcia-Castillo, J and Vallejo, DM and Da, Ros VG and Ballesta-Illan, E and Mihály, József and Dominguez, M}, doi = {10.1016/j.celrep.2018.02.049}, journal-iso = {CELL REP}, journal = {CELL REPORTS}, volume = {22}, unique-id = {3354869}, issn = {2211-1247}, abstract = {The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt- induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.}, year = {2018}, eissn = {2211-1247}, pages = {2541-2549} } @article{MTMT:3343168, title = {Microtubule organization in presynaptic boutons relies on the formin DAAM}, url = {https://m2.mtmt.hu/api/publication/3343168}, author = {Migh, Ede and Gotz, T and Földi, István and Szikora, Szilárd and Gombos, Rita I and Darula, Zsuzsanna and Medzihradszky F., Katalin and Maléth, József and Hegyi, Péter and Sigrist, S and Mihály, József}, doi = {10.1242/dev.158519}, journal-iso = {DEVELOPMENT}, journal = {DEVELOPMENT}, volume = {145}, unique-id = {3343168}, issn = {0950-1991}, abstract = {Regulation of the cytoskeleton is fundamental to the development and functioning of synaptic terminals, such as neuromuscular junctions. Nevertheless, despite identification of numerous proteins that regulate synaptic actin and microtubule dynamics, the mechanisms of cytoskeletal control during terminal arbor formation has remained largely elusive. Here, we show that DAAM, a member of the formin family of cytoskeleton organizing factors, is an important presynaptic regulator of neuromuscular junction development in Drosophila We demonstrate that the actin filament assembly activity of DAAM plays a negligible role in terminal formation; rather, DAAM is necessary for synaptic microtubule organization. Genetic interaction studies consistently link DAAM with the Wg/Ank2/Futsch module of microtubule regulation and bouton formation. Finally, we provide evidence that DAAM is tightly associated with the synaptic active zone scaffold, and electrophysiological data point to a role in the modulation of synaptic vesicle release. Based on these results, we propose that DAAM is an important cytoskeletal effector element of the Wg/Ank2 pathway involved in the determination of basic synaptic structures, and, additionally, DAAM may couple the active zone scaffold to the presynaptic cytoskeleton.}, year = {2018}, eissn = {1477-9129}, orcid-numbers = {Maléth, József/0000-0001-5768-3090; Hegyi, Péter/0000-0003-0399-7259} } @article{MTMT:3314386, title = {Formin’ bridges between microtubules and actin filaments in axonal growth cones}, url = {https://m2.mtmt.hu/api/publication/3314386}, author = {Földi, István and Szikora, Szilárd and Mihály, József}, doi = {10.4103/1673-5374.221148}, journal-iso = {NEUR REG RES}, journal = {NEURAL REGENERATION RESEARCH}, volume = {12}, unique-id = {3314386}, issn = {1673-5374}, year = {2017}, eissn = {1876-7958}, pages = {1971-1973} } @article{MTMT:3040810, title = {Unique and Overlapping Functions of Formins Frl and DAAM During Ommatidial Rotation and Neuronal Development in Drosophila.}, url = {https://m2.mtmt.hu/api/publication/3040810}, author = {Dollar, G and Gombos, Rita I and Barnett, AA and Sanchez, Hernandez D and Maung, SM and Mihály, József and Jenny, A}, doi = {10.1534/genetics.115.181438}, journal-iso = {GENETICS}, journal = {GENETICS}, volume = {202}, unique-id = {3040810}, issn = {0016-6731}, abstract = {The noncanonical Frizzled/planar cell polarity (PCP) pathway regulates establishment of polarity within the plane of an epithelium to generate diversity of cell fates, asymmetric, but highly aligned structures, or to orchestrate the directional migration of cells during convergent extension during vertebrate gastrulation. In Drosophila, PCP signaling is essential to orient actin wing hairs and to align ommatidia in the eye, in part by coordinating the movement of groups of photoreceptor cells during ommatidial rotation. Importantly, the coordination of PCP signaling with changes in the cytoskeleton is essential for proper epithelial polarity. Formins polymerize linear actin filaments and are key regulators of the actin cytoskeleton. Here, we show that the diaphanous-related formin, Frl, the single fly member of the FMNL (formin related in leukocytes/formin-like) formin subfamily affects ommatidial rotation in the Drosophila eye and is controlled by the Rho family GTPase Cdc42. Interestingly, we also found that frl mutants exhibit an axon growth phenotype in the mushroom body, a center for olfactory learning in the Drosophila brain, which is also affected in a subset of PCP genes. Significantly, Frl cooperates with Cdc42 and another formin, DAAM, during mushroom body formation. This study thus suggests that different formins can cooperate or act independently in distinct tissues, likely integrating various signaling inputs with the regulation of the cytoskeleton. It furthermore highlights the importance and complexity of formin-dependent cytoskeletal regulation in multiple organs and developmental contexts.}, year = {2016}, eissn = {1943-2631}, pages = {1135-1151} } @article{MTMT:3032868, title = {The Curcumin Analog C-150, Influencing NF-kappaB, UPR and Akt/Notch Pathways Has Potent Anticancer Activity In Vitro and In Vivo.}, url = {https://m2.mtmt.hu/api/publication/3032868}, author = {Hackler, L Jr and Ózsvári, Béla and Gyuris, M and Sipos, Péter and Fábián, Gabriella and Molnár, Eszter and Marton, Annamária and Faragó, Nóra and Mihály, József and Nagy, Lajos István and Szénási, Tibor and Diron, A and Párducz, Árpád and Kanizsai, Iván and Puskás, László}, doi = {10.1371/journal.pone.0149832}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {11}, unique-id = {3032868}, issn = {1932-6203}, abstract = {C-150 a Mannich-type curcumin derivative, exhibited pronounced cytotoxic effects against eight glioma cell lines at micromolar concentrations. Inhibition of cell proliferation by C-150 was mediated by affecting multiple targets as confirmed at transcription and protein level. C-150 effectively reduced the transcription activation of NFkB, inhibited PKC-alpha which are constitutively over-expressed in glioblastoma. The effects of C-150 on the Akt/ Notch signaling were also demonstrated in a Drosophila tumorigenesis model. C-150 reduced the number of tumors in Drosophila with similar efficacy to mitoxantrone. In an in vivo orthotopic glioma model, C-150 significantly increased the median survival of treated nude rats compared to control animals. The multi-target action of C-150, and its preliminary in vivo efficacy would render this curcumin analogue as a potent clinical candidate against glioblastoma.}, year = {2016}, eissn = {1932-6203}, orcid-numbers = {Ózsvári, Béla/0000-0001-9108-354X; Fábián, Gabriella/0000-0002-2323-4948; Szénási, Tibor/0000-0002-8405-0798} } @article{MTMT:2931297, title = {The Formin DAAM Functions as Molecular Effector of the Planar Cell Polarity Pathway during Axonal Development in Drosophila}, url = {https://m2.mtmt.hu/api/publication/2931297}, author = {Gombos, Rita I and Migh, Ede and Antal, Otilia Tamara and Mukherjee, A and Jenny, A and Mihály, József}, doi = {10.1523/JNEUROSCI.3708-14.2015}, journal-iso = {J NEUROSCI}, journal = {JOURNAL OF NEUROSCIENCE}, volume = {35}, unique-id = {2931297}, issn = {0270-6474}, abstract = {Recent studies established that the planar cell polarity (PCP) pathway is critical for various aspects of nervous system development and function, including axonal guidance. Although it seems clear that PCP signaling regulates actin dynamics, the mechanisms through which this occurs remain elusive. Here, we establish a functional link between the PCP system and one specific actin regulator, the formin DAAM, which has previously been shown to be required for embryonic axonal morphogenesis and filopodia formation in the growth cone. We show that dDAAM also plays a pivotal role during axonal growth and guidance in the adult Drosophila mushroom body, a brain center for learning and memory. By using a combination of genetic and biochemical assays, we demonstrate that Wnt5 and the PCP signaling proteins Frizzled, Strabismus, and Dishevelled act in concert with the small GTPase Rac1 to activate the actin assembly functions of dDAAM essential for correct targeting of mushroom body axons. Collectively, these data suggest that dDAAM is used as a major molecular effector of the PCP guidance pathway. By uncovering a signaling system from the Wnt5 guidance cue to an actin assembly factor, we propose that the Wnt5/PCP navigation system is linked by dDAAM to the regulation of the growth cone actin cytoskeleton, and thereby growth cone behavior, in a direct way.}, year = {2015}, eissn = {1529-2401}, pages = {10154-10167}, orcid-numbers = {Antal, Otilia Tamara/0000-0001-8321-5039} }