http://hdl.handle.net/10027/1377 Wed, 19 Jun 2013 10:37:47 GMT 2013-06-19T10:37:47Z http://hdl.handle.net/10027/8594 A common environmental carcinogen unduly affects carriers of cancer mutations: Carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen Friedenson, Bernard One way an inherited cancer gene mutation may target specific tissues for cancer is by increasing susceptibility when a tissue is exposed to environmental carcinogens. An example of this may be the increased susceptibility of BRCA1 or BRCA2 mutation carriers to the carcinogen formaldehyde. Formaldehyde is now a proven cause of human myeloid leukemias. Yet millions of tons of formaldehyde are produced every year and it is everywhere. High formaldehyde levels can overwhelm normal enzyme detoxification systems and cause DNA damage. It is known that some types of formaldehyde-associated DNA damage require error-free DNA repairs mediated by pathways containing BRCA1 and BRCA2 proteins. Otherwise some formaldehyde-related DNA damage cannot be properly repaired so mutations may occur. Therefore, carriers of BRCA1 and BRCA2 gene defects should be unduly susceptible to myeloid leukemia. Studies show that inherited biallelic BRCA2 gene defects dramatically increase risks for myeloid leukemia. Heterozygous BRCA1 or BRCA2 mutations also increase risks for myeloid leukemias in 11 of 12 relevant studies. BRCA1/2 mutation carriers may reduce risks for myeloid leukemias by using available precautions to lower their exposure to formaldehyde. NOTICE: this is the author’s version of a work that was accepted for publication in Medical Hypotheses. 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 Medical Hypotheses, [August 11, 2011] DOI: 10.1016/j.mehy.2011.07.039. The original publication is available at www.elsevier.com. Wed, 10 Aug 2011 05:00:00 GMT http://hdl.handle.net/10027/8594 2011-08-10T05:00:00Z http://hdl.handle.net/10027/8568 Suppression of FOXM1 Sensitizes Human Cancer Cells to Cell Death Induced by DNA-Damage Halasi, Marianna; Gartel, Andrei L. Irradiation and DNA-damaging chemotherapeutic agents are commonly used in anticancer treatments. Following DNA damage FOXM1 protein levels are often elevated. In this study, we sought to investigate the potential role of FOXM1 in programmed cell death induced by DNA-damage. Human cancer cells after FOXM1 suppression were subjected to doxorubicin or c-irradiation treatment. Our findings indicate that FOXM1 downregulation by stable or transient knockdown using RNAi or by treatment with proteasome inhibitors that target FOXM1 strongly sensitized human cancer cells of different origin to DNA-damage-induced apoptosis. We showed that FOXM1 suppresses the activation of pro-apoptotic JNK and positively regulates anti-apoptotic Bcl-2, suggesting that JNK activation and Bcl-2 down-regulation could mediate sensitivity to DNA-damaging agent-induced apoptosis after targeting FOXM1. Since FOXM1 is widely expressed in human cancers, our data further support the fact that it is a valid target for combinatorial anticancer therapy. © 2012 Halasi, Gartel. 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.0031761 Wed, 29 Feb 2012 06:00:00 GMT http://hdl.handle.net/10027/8568 2012-02-29T06:00:00Z http://hdl.handle.net/10027/8501 Bringing host-cell takeover by pathogenic bacteria to center stage: Editorial Dubreuil, Ron; Segev, Nava Intra-cellular pathogenic bacteria contrive processes in their host cell to create a niche for their own reproduction. One way that has emerged by which bacteria do that is delivery of secreted virulence factors, SVFs, to the cytoplasm of the host cells using the bacterial type IV secretion system, T4SS. These SVFs modulate the activity of their target host proteins, which in turn control key cellular processes. A major mechanism for the evolution of SVFs that modulate targets that do not exist in the bacterial kingdom is horizontal gene transfer. Recently, a number of bacterial SVFs were shown to act on two types of targets in host cells. First, a group of several SVFs modulate the activity and localization of one protein: Rab1 GTPase, a key regulator of intra-cellular trafficking. Second, ankyrin repeats-containing SVFs, referred to by microbiologists as Anks, interact with various binding proteins, which in turn regulate a myriad of cellular processes, including apoptosis. Modulation of trafficking and apoptosis are two examples of how invading bacteria takeover their host phagocyte, which instead of destroying the bacteria becomes a factory for its reproduction. © 2011 by Landes Bioscience, Cellular Logistics doi: 10.4161/cl.1.4.18984 Sat, 01 Jan 2011 06:00:00 GMT http://hdl.handle.net/10027/8501 2011-01-01T06:00:00Z http://hdl.handle.net/10027/8412 Regulation of Selective Autophagy Onset by a Ypt/Rab GTPase Module Lipatova, Zhanna; Belogortseva, Natalia; Zhang, Xiu Qi; Kim, Jane; Taussig, David; Segev, Nava The key regulators of intracellular trafficking, Ypt/Rab GTPases, are stimulated by specific upstream activators and, when activated, recruit specific downstream effectors to mediate membrane transport events. The yeast Ypt1 and its human functional homolog hRab1 regulate both endoplasmic reticulum (ER)-to-Golgi transport and autophagy. However, it is not clear whether the mechanism by which these GTPases regulate autophagy depends on their well-documented function in ER-to-Golgi transport. Here, we identify Atg11, the pre-autophagosomal structure (PAS) organizer, as a downstream effector of Ypt1 and show that the Ypt1-Atg11 interaction is required for PAS assembly under normal growth conditions. Moreover, we show that Ypt1 and Atg11 co-localize with Trs85, a Ypt1 activator subunit, and together they regulate selective autophagy. Finally, we show that Ypt1 and Trs85 interact on Atg9-containing membranes, which serve as a source for the membrane component of PAS. Together our results define the first Ypt/Rab module – comprising of activator, GTPase and effector – that orchestrates the onset of selective autophagy, a process vital for cell homeostasis. Furthermore, because Atg11 does not play a role in ER-to-Golgi transport, this is the first demonstration that Ypt/Rabs can regulate two independent membrane transport processes by recruiting process-specific effectors. © 2012 by National Academy of Sciences, Proceedings of the National Academy of Sciences doi: 10.1073/pnas.1121299109 Tue, 01 May 2012 05:00:00 GMT http://hdl.handle.net/10027/8412 2012-05-01T05:00:00Z