http://hdl.handle.net/10027/7341 Sun, 19 May 2013 23:40:27 GMT 2013-05-19T23:40:27Z http://hdl.handle.net/10027/8726 Knockdown of von Hippel-Lindau Protein decreases lung cancer cell proliferation and colonization Zhou, Qiyuan; Chen, Tianji; Ibe, Joyce Christina F.; Raj, J Usha; Zhou, Guofei Although von Hippel-Lindau protein (pVHL) is known as a tumor suppressor in kidney and other organs, it remains unclear whether pVHL plays a role in lung cancer development. We investigated the role of pVHL in lung cancer cell proliferation, migration, and colonization using stable A549 cells with knockdown of pVHL. We found that knockdown of pVHL promotes epithelial-mesenchymal transition (EMT) in lung cancer cells. Knockdown of pVHL decreased tumor colonization in a tail-vein injection model and decreased cell proliferation, whereas overexpression of constitutive active HIF increased tumor colonization, suggesting a HIF-independent function of pVHL in lung. Knockdown of pVHL decreased phosphorylation of FAK and expression of integrin, suggesting that pVHL regulates lung cancer development via integrin/FAK signaling pathway. NOTICE: this is the author’s version of a work that was accepted for publication in FEBS Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in FEBS Letters, [Vol 586, Issue 10, 2012, May] DOI:10.1016/j.febslet.2012.04.009 Tue, 01 May 2012 05:00:00 GMT http://hdl.handle.net/10027/8726 2012-05-01T05:00:00Z http://hdl.handle.net/10027/8721 Hypoxia modulates the expression of leucine zipper-positive MYPT1 and its interaction with protein kinase G and Rho kinases in pulmonary arterial smooth muscle cells. Singh, Dev K.; Sarkar, Joy; Raghavan, Aarti; Reddy, Sekhar P.; Raj, J. Usha We have shown previously that acute hypoxia downregulates protein kinase G (PKG) expression and activity in ovine fetal pulmonary vessels and pulmonary arterial smooth muscle cells (SMC). Here, we report that acute hypoxia also reduces the expression of leucinezipper-positive MYPT1 (LZ(+)MYPT1), a subunit of myosin light chain (MLC) phosphatase, in ovine fetal pulmonary arterial SMC. We found that in hypoxia, there is greater interaction between LZ(+) MYPT1 and RhoA and Rho kinase 1 (ROCK1)/Rho kinase 2 (ROCK2) and decreased interaction between LZ(+) MYPT1 and PKG, resulting in increased MLC(20) phosphorylation, a higher pMLC(20)/MLC(20) ratio and SMC contraction. In normoxic SMC PKG overexpression, LZ(+) MYPT1 expression is upregulated while PKG knockdown had an opposite effect. LZ(+) MYPT1 overexpression enhanced the interaction between PKG and LZ(+) MYPT1. Overexpression of a mutant LZ(-) MYPT1 isoform in SMC mimicked the effects of acute hypoxia and decreased pMLC(20)/MLC(20) ratio. Collectively, our data suggest that hypoxia downregulates LZ(+) MYPT1 expression by suppressing PKG levels, reduces the interaction of LZ(+) MYPT1 with PKG and promotes LZ(+) MYPT1 interaction with RhoA or ROCK1/ROCK2, thereby promoting pulmonary arterial SMC contraction. This is a copy of an article published in the Pulmonary Circulation © 2011 Medknow Publications. DOI: 10.4103/2045-8932.93548 Sat, 01 Oct 2011 05:00:00 GMT http://hdl.handle.net/10027/8721 2011-10-01T05:00:00Z http://hdl.handle.net/10027/8614 Targeted Deletion of Jun/AP-1 in Alveolar Epithelial Cells Causes Progressive Emphysema and Worsens Cigarette Smoke-Induced Lung Inflammation Reddy, Narsa M.; Vegiraju, Suryanaraya; Irving, Ashley; Paun, Bogdan C.; Luzina, Irina G.; Atamas, Sergei P.; Biswal, Shyam; Ana, Navas-Acien; Mitzner, Wayne; Reddy, Sekhar P. The c-Jun/AP-1 transcriptional factor is known to regulate cell proliferation, apoptosis, and inflammatory responses; however its role in lung pathogenesis is largely unknown. Here we report that the declined expression levels of c-Jun mRNA and protein in the lung tissues of advanced chronic obstructive pulmonary disease (COPD) patients, and that genetic deletion of c-Jun specifically in alveolar epithelial cells causes progressive emphysema with lung inflammation and alveolar air space enlargement, which are cardinal features of emphysema. Although mice lacking c-Jun specifically in lung alveolar epithelial cells appear normal at 6 weeks of age, when exposed to chronic cigarette smoke, c-Jun mutant mice display more lung inflammation with perivascular and peribronchiolar infiltrates. These results demonstrate that the c-Jun/AP-1 pathway is critical for maintaining lung alveolar cell homeostasis and that loss of its expression can contribute to lung inflammation and progressive emphysema. NOTICE: this is the author’s version of a work that was accepted for publication in the American Journal of Pathology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in the American Journal of Pathology, Vol 180, Issue 2, Feb 2012. DOI: 10.1016/j.ajpath.2011.10.029 Wed, 01 Feb 2012 06:00:00 GMT http://hdl.handle.net/10027/8614 2012-02-01T06:00:00Z http://hdl.handle.net/10027/8548 Genetic Associations in the Vitamin D Receptor and Colorectal Cancer in African Americans and Caucasians Kupfer, Sonia S.; Anderson, Jeffrey R.; Ludvik, Anton E.; Hooker, Stanley; Skol, Andrew; Kittles, Rick A.; Keku, Temitope O.; Sandler, Robert S.; Ruiz-Ponte, Clara; Castellvi-Bel, Sergi; Castells, Antoni; Carracedo, Angel; Ellis, Nathan A. Low vitamin D levels are associated with an increased incidence of colorectal cancer (CRC) and higher mortality from the disease. In the US, African Americans (AAs) have the highest CRC incidence and mortality and the lowest levels of vitamin D. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been previously associated with CRC, but few studies have included AAs. We studied 795 AA CRC cases and 985 AA controls from Chicago and North Carolina as well as 1324 Caucasian cases and 990 Caucasian controls from Chicago and Spain. We genotyped 54 tagSNPs in VDR (46586959 to 46521297 Mb) and tested for association adjusting for West African ancestry, age, gender, and multiple testing. Untyped markers were imputed using MACH1.0. We analyzed associations by gender and anatomic location in the whole study group as well as by vitamin D intake in the North Carolina AA group. In the joint analysis, none of the SNPs tested was significantly associated with CRC. For four previously tested restriction fragment length polymorphisms, only one (referred to as ApaI), tagged by the SNP rs79628898, had a nominally significant p-value in AAs; none of these polymorphisms were associated with CRC in Caucasians. In the North Carolina AAs, for whom we had vitamin D intake data, we found a significant association between an intronic SNP rs11574041 and vitamin D intake, which is evidence for a VDR gene-environment interaction in AAs. In summary, using a systematic tagSNP approach, we have not found evidence for significant associations between VDR and CRC in AAs or Caucasians. © 2011 Kupfer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. doi:10.1371/journal.pone.0026123 Thu, 27 Oct 2011 05:00:00 GMT http://hdl.handle.net/10027/8548 2011-10-27T05:00:00Z