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Stuart G Jarrett, Erin M Wolf Horrell, John A D'Orazio
Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER)...
September 28, 2016: Nucleic Acids Research
J Kang, W Kim, S Lee, D Kwon, J Chun, B Son, E Kim, J-M Lee, H Youn, B Youn
Non-small cell lung cancer (NSCLC) remains one of the leading causes of death worldwide, and thus new molecular targets need to be identified to improve treatment efficacy. Although epidermal growth factor receptor (EGFR)/KRAS mutation-driven lung tumorigenesis is well understood, the mechanism of EGFR/KRAS-independent signal activation remains elusive. Enhanced TFAP2C (transcription factor activating enhancer-binding protein 2C) expression is associated with poor prognosis in some types of cancer patients, but little is known of its relation with the pathogenesis of lung cancer...
September 5, 2016: Oncogene
Claudia Barzago, Josephine Lum, Paola Cavalcante, Kandhadayar Gopalan Srinivasan, Elisa Faggiani, Giorgia Camera, Silvia Bonanno, Francesca Andreetta, Carlo Antozzi, Fulvio Baggi, Raffaele Adolfo Calogero, Pia Bernasconi, Renato Mantegazza, Lucia Mori, Francesca Zolezzi
Myasthenia gravis (MG) is a T-cell dependent autoimmune disorder of the neuromuscular junction, characterised by muscle weakness and fatigability. Autoimmunity is thought to initiate in the thymus of acetylcholine receptor (AChR)-positive MG patients; however, the molecular mechanisms linking intra-thymic MG pathogenesis with autoreactivity via the circulation to the muscle target organ are poorly understood. Using whole-transcriptome sequencing, we compared the transcriptional profile of peripheral blood mononuclear cells from AChR-early onset MG (AChR-EOMG) patients with healthy controls: 178 coding transcripts and 229 long non-coding RNAs, including 11 pre-miRNAs, were differentially expressed...
November 2016: Immunobiology
Onder Bozdogan, Ibrahim Vargel, Tarik Cavusoglu, Ayse A Karabulut, Gurbet Karahan, Nilufer Sayar, Pınar Atasoy, Isik G Yulug
Cutaneous squamous cell carcinomas (cSCCs) are common human carcinomas. Despite having metastasizing capacities, they usually show less aggressive progression compared to squamous cell carcinoma (SCC) of other organs. Metastasis suppressor proteins (MSPs) are a group of proteins that control and slow-down the metastatic process. In this study, we established the importance of seven well-defined MSPs including NDRG1, NM23-H1, RhoGDI2, E-cadherin, CD82/KAI1, MKK4, and AKAP12 in cSCCs. Protein expression levels of the selected MSPs were detected in 32 cSCCs, 6 in situ SCCs, and two skin cell lines (HaCaT, A-431) by immunohistochemistry...
July 2016: Pathology, Research and Practice
Thomas Wilhelm, Daniel B Lipka, Tania Witte, Justyna A Wierzbinska, Silvia Fluhr, Monika Helf, Oliver Mücke, Rainer Claus, Carolin Konermann, Peter Nöllke, Charlotte M Niemeyer, Christian Flotho, Christoph Plass
A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative high-resolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., α, β, and γ) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples...
2016: Epigenetics: Official Journal of the DNA Methylation Society
P Peixoto, A Blomme, B Costanza, R Ronca, S Rezzola, A P Palacios, L Schoysman, S Boutry, N Goffart, O Peulen, P Maris, E Di Valentin, V Hennequière, E Bianchi, A Henry, P Meunier, B Rogister, R N Muller, P Delvenne, A Bellahcène, V Castronovo, A Turtoi
To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53...
August 25, 2016: Oncogene
Micah B Schott, Faith Gonowolo, Benjamin Maliske, Bryon Grove
Scaffold proteins play a critical role in cellular homeostasis by anchoring signaling enzymes in close proximity to downstream effectors. In addition to anchoring static enzyme complexes, some scaffold proteins also form dynamic signalosomes that can traffic to different subcellular compartments upon stimulation. Gravin (AKAP12), a multivalent scaffold, anchors PKA and other enzymes to the plasma membrane under basal conditions, but upon [Ca(2+)]i elevation, is rapidly redistributed to the cytosol. Because gravin redistribution also impacts PKA localization, we postulate that gravin acts as a calcium "switch" that modulates PKA-substrate interactions at the plasma membrane, thus facilitating a novel crosstalk mechanism between Ca(2+) and PKA-dependent pathways...
April 2016: Cellular Signalling
Peng Zhao, Juanling Fu, Biyun Yao, Yongrui Jia, Hongtao Zhang, Xuehui Li, Lisha Dong, Ya Gao, Wenli Liu, Wen Chen, Zongcan Zhou
To screen potential biomarkers of benzo(a)pyrene (BaP)-induced lung cancer, the proteomic profiles of BaP-transformed 16HBE cell line T-16HBE-C1 cells serum-free culture supernatant and xenografted nude mice sera were compared with those of 16HBE group by utilizing label-free quantitative proteomic strategy. By employing nano-LC-MS/MS technology followed by MaxQuant and Perseus processing, 489 differentially expressed proteins were identified between T-16HBE-C1 and 16HBE cells serum-free culture supernatant, and 49 significantly up-regulated proteins were identified in T-16HBE-C1 xenografted nude mice sera...
February 5, 2016: Chemico-biological Interactions
Wei Xia, Jing Ni, Juhua Zhuang, Leixing Qian, Peng Wang, Jiening Wang
AKAP12/Gravin (A kinase anchor protein 12) belongs to the group of A-kinase scaffold proteins and functions as a tumor suppressor in some human primary cancers. While AKAP12 is found consistently downregulated in hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis has not been fully elucidated. We identified targeting sites for miR-103 in the 3'-untranslated region (3'-UTR) of AKAP12 by bioinformatic analysis and confirm their function by a luciferase reporter gene assay. We reveal miR-103 expression to be inversely correlated with AKAP12 in HCC tissue samples and show that overexpressed miR-103 promotes cell proliferation and inhibits apoptosis by downregulating AKAP12 expression in HCC cell lines...
February 2016: International Journal of Biochemistry & Cell Biology
Yaqiong Sun, Chuanzhong Ye, Xingyi Guo, Wanqing Wen, Jirong Long, Yu-Tang Gao, Xiao Ou Shu, Wei Zheng, Qiuyin Cai
In a genome-wide association study conducted among Chinese women, we identified the single nucleotide polymorphism (SNP) rs2046210 at 6q25.1 for breast cancer risk. To explore a potential regulatory role for this risk locus, we measured expression levels of nine genes at the locus in breast cancer tissue and adjacent normal tissue samples obtained from 67 patients recruited in the Shanghai Breast Cancer Study. We found that rs2046210 had a statistically significant association with the expression levels of the AKAP12 and ESR1 genes in adjacent normal breast tissues...
February 2016: Carcinogenesis
Heidi Hehnly, David Canton, Paula Bucko, Lorene K Langeberg, Leah Ogier, Irwin Gelman, L Fernando Santana, Linda Wordeman, John D Scott
Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase...
September 25, 2015: ELife
B Han, W J Poppinga, M Schmidt
Cell division relies on coordinated regulation of the cell cycle. A process including a well-defined series of strictly regulated molecular mechanisms involving cyclin-dependent kinases, retinoblastoma protein, and polo-like kinases. Dysfunctions in cell cycle regulation are associated with disease such as cancer, diabetes, and neurodegeneration. Compartmentalization of cellular signaling is a common strategy used to ensure the accuracy and efficiency of cellular responses. Compartmentalization of intracellular signaling is maintained by scaffolding proteins, such as A-kinase anchoring proteins (AKAPs)...
December 2015: Pflügers Archiv: European Journal of Physiology
He Ma, Ting Lu, Xiaojin Zhang, Chuanfu Li, Jingwei Xiong, Lei Huang, Ping Liu, Yuehua Li, Li Liu, Zhengnian Ding
Lung tumor progression is regulated by proangiogenic factors. Heat shock protein A12B (HSPA12B) is a recently identified regulator of expression of proangiogenic factors. However, whether HSPA12B plays a role in lung tumor growth is unknown. To address this question, transgenic mice overexpressing HSPA12B (Tg) and wild-type littermates (WT) were implanted with Lewis lung cancer cells to induce lung tumorigenesis. Tg mice showed significantly higher number and bigger size of tumors than WT mice. Tg tumors exhibited increased angiogenesis and proliferation while reduced apoptosis compared with WT tumors...
April 30, 2015: Oncotarget
Elizabeth C Finger, Laura Castellini, Erinn B Rankin, Marta Vilalta, Adam J Krieg, Dadi Jiang, Alice Banh, Wayne Zundel, Marianne Broome Powell, Amato J Giaccia
Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (A-kinase anchor protein 12), AKAP12v2, in metastatic melanoma...
April 7, 2015: Proceedings of the National Academy of Sciences of the United States of America
K L Ellis, Y Zhou, J R Beshansky, E Ainehsazan, H P Selker, L A Cupples, G S Huggins, I Peter
Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n = 318), we explored effects of 132,634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-associated variants and infarct size (n = 84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P2df ⩽ 4...
December 2015: Pharmacogenomics Journal
Nicholas W Bateman, Elizabeth Jaworski, Wei Ao, Guisong Wang, Tracy Litzi, Elizabeth Dubil, Charlotte Marcus, Kelly A Conrads, Pang-ning Teng, Brian L Hood, Neil T Phippen, Lisa A Vasicek, William P McGuire, Keren Paz, David Sidransky, Chad A Hamilton, G Larry Maxwell, Kathleen M Darcy, Thomas P Conrads
A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient...
April 3, 2015: Journal of Proteome Research
(no author information available yet)
No abstract text is available yet for this article.
February 2015: Journal of Crohn's & Colitis
Hyun-Ho Kim, Jeong-gyun Kim, Jinkyung Jeong, Song-Yi Han, Kyu-Won Kim
Swimming behavior in fish is driven by coordinated contractions of muscle fibers. In zebrafish, slow muscle cell migration is crucial for the formation of the muscle network; slow myoblasts, which arise from medial adaxial cells, migrate radially to the lateral surface of the trunk and tail during embryogenesis. This study found that the zebrafish A-kinase anchoring protein (akap)12 isoforms akap12α and akap12β are required for muscle morphogenesis and locomotor activity. Embryos deficient in akap12 exhibited reduced spontaneous coiling, touch response, and free swimming...
November 2014: Differentiation; Research in Biological Diversity
Onder Bozdogan, Isik G Yulug, Ibrahim Vargel, Tarik Cavusoglu, Ayse A Karabulut, Gurbet Karahan, Nilufer Sayar
BACKGROUND: Basal cell carcinomas (BCCs) are common malignant skin tumors. Despite having a significant invasion capacity, they metastasize only rarely. Our aim in this study was to detect the expression patterns of the NM23-H1, NDRG1, E-cadherin, RHOGDI2, CD82/KAI1, MKK4, and AKAP12 metastasis suppressor proteins in BCCs. METHODS: A total of 96 BCC and 10 normal skin samples were included for the immunohistochemical study. Eleven frozen BCC samples were also studied by quantitative real time polymerase chain reaction (qRT-PCR) to detect the gene expression profile...
August 2015: International Journal of Dermatology
Nili Avidan, Rozen Le Panse, Hanne F Harbo, Pia Bernasconi, Konstantinos Poulas, Elizabeta Ginzburg, Paola Cavalcante, Lara Colleoni, Fulvio Baggi, Carlo Antozzi, Frédérique Truffault, Shirley Horn-Saban, Simone Pöschel, Zoi Zagoriti, Angelina Maniaol, Benedicte A Lie, Isabelle Bernard, Abdelhadi Saoudi, Zsolt Illes, Carlos Casasnovas Pons, Arthur Melms, Socrates Tzartos, Nicholas Willcox, Anna Kostera-Pruszczyk, Chantal Tallaksen, Renato Mantegazza, Sonia Berrih-Aknin, Ariel Miller
OBJECTIVE: To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy. METHODS: Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes...
May 2014: Annals of Clinical and Translational Neurology
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