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Salvador Alonso, Daniela Hernandez, Yu-Ting Chang, Christian D Gocke, Megan McCray, Ravi Varadhan, William H Matsui, Richard J Jones, Gabriel Ghiaur
Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid-low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche...
October 24, 2016: Journal of Clinical Investigation
Simone Manzocchi, Luigi Venco, Angela Di Cesare
No abstract text is available yet for this article.
October 23, 2016: Veterinary Clinical Pathology
Francisca Leal, Martin J Cohn
Limb reduction and loss are hallmarks of snake evolution. Although advanced snakes are completely limbless, basal and intermediate snakes retain pelvic girdles and small rudiments of the femur. Moreover, legs may have re-emerged in extinct snake lineages [1-5], suggesting that the mechanisms of limb development were not completely lost in snakes. Here we report that hindlimb development arrests in python embryos as a result of mutations that abolish essential transcription factor binding sites in the limb-specific enhancer of Sonic hedgehog (SHH)...
October 19, 2016: Current Biology: CB
Magda Langiewicz, Andrea Schlegel, Enrica Saponara, Michael Linecker, Pieter Borger, Rolf Graf, Bostjan Humar, Pierre A Clavien
BACKGROUND & AIMS: Occlusion of one liver section by portal vein ligation (PVL) induces compensatory liver regeneration in the remaining part. PVL-induced liver growth is being exploited for the surgical removal of large/multiple liver tumors. A novel approach coined ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) combines PVL with parenchymal transection and massively accelerates compensatory growth, enabling much faster and more extensive tumor removal...
October 19, 2016: Journal of Hepatology
Evgeny Z Kvon, Olga K Kamneva, Uirá S Melo, Iros Barozzi, Marco Osterwalder, Brandon J Mannion, Virginie Tissières, Catherine S Pickle, Ingrid Plajzer-Frick, Elizabeth A Lee, Momoe Kato, Tyler H Garvin, Jennifer A Akiyama, Veena Afzal, Javier Lopez-Rios, Edward M Rubin, Diane E Dickel, Len A Pennacchio, Axel Visel
The evolution of body shape is thought to be tightly coupled to changes in regulatory sequences, but specific molecular events associated with major morphological transitions in vertebrates have remained elusive. We identified snake-specific sequence changes within an otherwise highly conserved long-range limb enhancer of Sonic hedgehog (Shh). Transgenic mouse reporter assays revealed that the in vivo activity pattern of the enhancer is conserved across a wide range of vertebrates, including fish, but not in snakes...
October 20, 2016: Cell
Mu He, Stephanie Agbu, Kathryn V Anderson
The mammalian Hedgehog (Hh) signaling pathway is required for development and for maintenance of adult stem cells, and overactivation of the pathway can cause tumorigenesis. All responses to Hh family ligands in mammals require the primary cilium, an ancient microtubule-based organelle that extends from the cell surface. Genetic studies in mice and humans have defined specific functions for cilium-associated microtubule motor proteins: they act in the construction and disassembly of the primary cilium, they control ciliary length and stability, and some have direct roles in mammalian Hh signal transduction...
October 17, 2016: Trends in Cell Biology
Suzanne Gonzalez, Jayanta Gupta, Erika Villa, Indika Mallawaarachchi, Marco Rodriguez, Mercedes Ramirez, Juan Zavala, Regina Armas, Albana Dassori, Javier Contreras, Deborah Flores, Alvaro Jerez, Alfonso Ontiveros, Humberto Nicolini, Michael Escamilla
OBJECTIVES: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD...
September 2016: Bipolar Disorders
Yan Wang, Jung-Mao Hsu, Ya'an Kang, Yongkun Wei, Pei-Chih Lee, Shing-Jyh Chang, Yi-Hsin Hsu, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Chia-Wei Li, Hsin-Wei Liao, Shih-Shin Chang, Weiya Xia, How-Wen Ko, Chao-Kai Chou, Jason B Fleming, Huamin Wang, Rosa F Hwang, Yue Chen, Jun Qin, Mien-Chie Hung
The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). While TGF-β and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understood how Gli1 functional activity is regulated. Here we report the identification of Gli1 as a substrate for the protein arginine N-methyltransferase PRMT1 in PDAC. We found that PRMT1 methylates Gli1 at R597, promoting its transcriptional activity by enhancing the binding of Gli1 to its target gene promoters...
October 6, 2016: Cancer Research
Guangzhi Zhang, Richard Ducatelle, Belgacem Mihi, Annemieke Smet, Bram Flahou, Freddy Haesebrouck
The stomach of pigs at slaughter age is often colonized by Helicobacter (H.) suis, which is also the most prevalent gastric non-H. pylori Helicobacter (NHPH) species in humans. It is associated with chronic gastritis, gastric ulceration and other gastric pathological changes in both hosts. Parietal cells are highly specialized, terminally differentiated epithelial cells responsible for gastric acid secretion and regulation. Dysfunction of these cells is closely associated with gastric pathology and disease...
October 19, 2016: Veterinary Research
Wang Zheng, Jungwoo Yang, Erwan Beauchamp, Ruiqi Cai, Shaimaa Hussein, Laura Hofmann, Qiang Li, Veit Flockerzi, Luc G Berthiaume, Jingfeng Tang, Xing-Zhen Chen
Transient receptor potential polycystin-3 (TRPP3) is a cation channel activated by calcium and proton and is involved in hedgehog signaling, intestinal development, and sour tasting. How TRPP3 channel function is regulated remains poorly understood. By N-terminal truncation mutations, electrophysiology and Xenopus oocytes expression, we first identified fragment D21-S42 to be functionally important. We then found that deletion mutant Δ1-36 (TRPP3 missing fragment M1-R36) has similar function as wild-type TRPP3 while Δ1-38 is functionally dead, suggesting the importance of V37 or C38...
October 17, 2016: Journal of Biological Chemistry
Jun Yang, Wenjing Huang, Wenfu Tan
The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1...
October 14, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Qian Sun, Jing Bai, Renrong Lv
Since hedgehog (HH)/Gli1 that contributes to cancer proliferation and metastasis has been masked for decades, the signaling pathway was investigated about its exact role in proliferation and metastasis of cutaneous squamous cell carcinoma (SCC). Sonic hedgehog homolog (Shh), GLI family zinc finger 1 (Gli1), and vascular endothelial growth factor (VEGF) expressions in cutaneous SCC tissues were analyzed with immunohistochemistry, and their correlations with cutaneous SCC patients' prognosis were conducted with Kaplan-Meier curve...
October 17, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Elissaveta Petrova, Arne Scholz, Juliane Paul, Andrea Sturz, Katja Haike, Franziska Siegel, Dominik Mumberg, Ningshu Liu
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects...
October 13, 2016: Oncotarget
Daniel Konstantinou, Nina Bertaux-Skeirik, Yana Zavros
The Hedgehog (Hh) signaling pathway not only plays a key part in controlling embryonic development, but in the adult stomach governs important cellular events such as epithelial cell differentiation, proliferation, gastric disease, and regeneration. In particular, Sonic Hedgehog (Shh) signaling has been well studied for its role in gastric physiology and pathophysiology. Shh is secreted from the gastric parietal cells and contributes to the regeneration of the epithelium in response to injury, or the development of gastritis during Helicobacter pylori infection...
October 14, 2016: Current Opinion in Pharmacology
F Faião-Flores, D K Alves-Fernandes, P C Pennacchi, S Sandri, A L S A Vicente, C Scapulatempo-Neto, V L Vazquez, R M Reis, J Chauhan, C R Goding, K S Smalley, S S Maria-Engler
BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells...
October 17, 2016: Oncogene
Guoqiang Ma, Shuang Li, Yuhong Han, Shuangxi Li, Tao Yue, Bing Wang, Jin Jiang
Hedgehog (Hh) signaling plays a central role in development and diseases. Hh activates its signal transducer and GPCR-family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is activated through other post-translational modifications remains unexplored. Here we show that sumoylation acts in parallel with phosphorylation to promote Smo cell-surface expression and Hh signaling. We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation enzyme Ulp1. Sumoylation of Smo in turn recruits a deubiquitinase UBPY/USP8 to antagonize Smo ubiquitination and degradation, leading to its cell-surface accumulation and elevated Hh pathway activity...
October 7, 2016: Developmental Cell
Heng Cai, Hongxing Li, Jingmin Li, Xiaoyan Li, Yana Li, Yan Shi, Dong Wang
Although abnormal activation of the sonic hedgehog (Shh) signaling pathway has been demonstrated in human hepatocellular carcinoma (HCC) patients and in most HCC cell lines, the mechanism by which the Shh pathway promotes the development of HCC remains uncertain. Using a liver cancer model induced by diethylnitrosamine (DEN) which mimics the process from liver injury, abnormal hepatocyte proliferation, and hepatocirrhosis to hepatocyte canceration, we investigated the abnormal activation of the Shh pathway by examining the expression of Shh, patched-1 (Ptch), smoothened (SMO), and glioma-associated oncogene-1 (Gli1) genes...
October 15, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Haolin Chen, Yiyan Wang, Renshan Ge, Barry R Zirkin
Adult Leydig cells develop from undifferentiated mesenchymal-like stem cells (stem Leydig cells, SLCs) present in the interstitial compartment of the early postnatal testis. Putative SLCs also have been identified in peritubular and perivascular locations of the adult testis. The latter cells, which normally are quiescent, are capable of regenerating new Leydig cells upon the loss of the adult cells. Recent studies have identified several protein markers to identify these cells, including nestin, PDGFRα, COUP-TFII, CD51 and CD90...
October 12, 2016: Molecular and Cellular Endocrinology
Xu Zhang, Qianni Cheng, Yixiang Wang, Po Sing Leung, Kinglun Kingston Mak
Bone plays a role in energy metabolism, but the interplay between bone and other organs in this process is not completely understood. Here, we show that upregulated Hh signaling in bones results in increased whole-body energy expenditure, white adipose tissue (WAT) browning, hypoglycemia and skeletal muscle atrophy. We found that Hh signaling induces PTHrP secretion from bones and causes WAT browning. Injection of PTHrP-neutralizing antibody attenuates WAT browning and improves the circulating blood glucose level while high-fat diet treatment only rescues hypoglycemia...
October 14, 2016: Cell Death and Differentiation
Shellese A Cannonier, Cara B Gonzales, Kim Ely, Scott A Guelcher, Julie A Sterling
Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood...
October 12, 2016: Oncotarget
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