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Transcriptional Repression of E-Cadherin by Human Papillomavirus Type 16 E6
(Public Library of Science, 2012) D’Costa, Zarina J.; Jolly, Carol; Androphy, Elliot J.; Mercer, Andrew; Matthews, Charles M.; Hibma, Merilyn H.; Dermatology, School of Medicine
There is increasing evidence supporting DNA virus regulation of the cell adhesion and tumour suppressor protein, E-cadherin. We previously reported that loss of E-cadherin in human papillomavirus (HPV) type 16-infected epidermis is contributed to by the major viral proto-oncogene E6 and is associated with reduced Langerhans cells density, potentially regulating the immune response. The focus of this study is determining how the HPV16 E6 protein mediates E-cadherin repression. We found that the E-cadherin promoter is repressed in cells expressing E6, resulting in fewer E-cadherin transcripts. On exploring the mechanism for this, repression by increased histone deacetylase activity or by increased binding of trans-repressors to the E-cadherin promoter Epal element was discounted. In contrast, DNA methyltransferase (DNMT) activity was increased in E6 expressing cells. Upon inhibiting DNMT activity using 5-Aza-2'-deoxycytidine, E-cadherin transcription was restored in the presence of HPV16 E6. The E-cadherin promoter was not directly methylated, however a mutational analysis showed general promoter repression and reduced binding of the transactivators Sp1 and AML1 and the repressor Slug. Expression of E7 with E6 resulted in a further reduction in surface E-cadherin levels. This is the first report of HPV16 E6-mediated transcriptional repression of this adhesion molecule and tumour suppressor protein.
Chronic Anticholinergic Use and the Aging Brain
(Wiley, 2013) Cai, Xueya; Campbell, Noll; Khan, Babar; Callahan, Chris; Boustani, Malaz; Medicine, School of Medicine
Background: Older Americans are facing an epidemic of chronic diseases and are thus exposed to anticholinergics (ACs) that might negatively affect their risk of developing mild cognitive impairment (MCI) or dementia.
Objective: To investigate the association between impairment in cognitive function and previous AC exposure.
Design: A retrospective cohort study.
Setting: Primary care clinics in Indianapolis, Indiana.
Participants: A total of 3690 older adults who have undergone cognitive assessment and had a 1-year medication-dispensing record.
Outcome: Cognitive function was measured in two sequential steps: a two-step screening process followed by a formal diagnostic process for participants with positive screening results.
Exposure: Three patterns of AC exposure were defined by the duration of AC exposure, the number of AC medications dispensed at the same time, and the severity of AC effects as determined by the Anticholinergic Cognitive Burden list.
Results: Compared with older adults with no AC exposure and after adjusting for age, race, gender, and underlying comorbidity, the odds ratio for having a diagnosis of MCI was 2.73 (95% confidence interval, 1.27-5.87) among older adults who were exposed to at least three possible ACs for at least 90 days; the odds ratio for having dementia was 0.43 (95% confidence interval, 0.10-1.81).
Conclusion: Exposure to medications with severe AC cognitive burden may be a risk factor for developing MCI.
Mediator and SAGA Have Distinct Roles in Pol II Preinitiation Complex Assembly and Function
(Elsevier, 2012) Chen, Xiao-Fen; Lehmann, Lynn; Lin, Justin J.; Vashisht, Ajay; Schmidt, Ryan; Ferrari, Roberto; Huang, Chengyang; McKee, Robin; Mosley, Amber; Plath, Kathrin; Kurdistani, Siavash K.; Wohlschlegel, James; Carey, Michael; Biochemistry and Molecular Biology, School of Medicine
A key feature of RNA polymerase II preinitiation complexes (PICs) is their ability to coordinate transcription initiation with chromatin modification and remodeling. To understand how this coordination is achieved, we employed extensive proteomic and mechanistic analyses to study the composition and assembly of PICs in HeLa and mouse embryonic stem (ES) cell nuclear extracts. Strikingly, most of the machinery necessary for transcription initiation on chromatin is part of the PIC. The PIC is nearly identical between ES and HeLa cells, and contains two major co-activator complexes, Mediator and SAGA. Genomewide analysis of Mediator reveals a close correlation with Pol II, TBP and mRNA levels implying a major role in PIC assembly. Moreover, Mediator coordinates assembly of the Pol II initiation factors and chromatin machinery into a PIC in vitro, while SAGA acts after PIC assembly to allow transcription on chromatin.
PPARγ Agonists Promote Oligodendrocyte Differentiation of Neural Stem Cells by Modulating Stemness and Differentiation Genes
(Public Library of Science, 2012) Kanakasabai, Saravanan; Pestereva, Ecaterina; Chearwae, Wanida; Gupta, Sushil K.; Ansari, Saif; Bright, John J.; Medicine, School of Medicine
Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ(12,14)-Prostaglandin J(2) (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3-7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3-7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.
The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance)
(Wolters Kluwer, 2013) Lewis, Lionel D.; Miller, Antonius A.; Owzar, Kouros; Bies, Robert R.; Markova, Svetlana; Jiang, Chen; Kroetz, Deanna L.; Egorin, Merrill J.; McLeod, Howard L.; Ratain, Mark J.; Alliance for Clinical Trials in Oncology; Medicine, School of Medicine
Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.