The Wnt/β-catenin/Tcf and IκB/NF-κB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/β-catenin signaling occurs in ...certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear β-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IκB kinase complex (IKK) that phosphorylates IκB contains IKKα, IKKβ, and IKKγ. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/β-catenin and IκB pathways in mitogenic signaling. Mitogenic induction of G
1
-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1
−/−
cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IκB/IKKα or β-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKα. In IKKα
−/−
cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKα restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKα
−/−
cells, β-catenin phosphorylation was decreased and purified IKKα was sufficient for phosphorylation of β-catenin through its N-terminus in vitro. Because IKKα but not IKKβ induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKα and IKKβ may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.
Human APC2 localization and allelic imbalance JARRETT, Christy Rothwell; BLANCATO, Jan; TIN CAO ...
Cancer research (Chicago, Ill.),
11/2001, Letnik:
61, Številka:
21
Journal Article
Recenzirano
A second adenomatous polyposis coli (APC)-like gene, APC2/APCL, was recently described and localized to chromosome 19. We have fine mapped APC2 to a small region of chromosome 19p13.3 containing ...markers D19S883 and WI-19632, a region commonly lost in a variety of cancers, particularly ovarian cancer. Interphase fluorescence in situ hybridization analysis revealed an APC2 allelic imbalance in 19 of 20 ovarian cancers screened and indicates that APC2 could be a potential tumor suppressor gene in ovarian cancer. When overexpressed in SKOV3 ovarian cancer cells, which express low levels of APC2, exogenous APC2 localized to the Golgi apparatus, actin-containing structures, and occasionally to microtubules. Antibodies against the NH2 terminus of human APC2 show that endogenous APC2 is diffusely distributed in the cytoplasm and colocalizes with both the Golgi apparatus and actin filaments. APC2 remained associated with actin filaments after treatment with the actin-disrupting agent, cytochalasin D. These results suggest that APC2 is involved in actin-associated events and could influence cell motility or adhesion through interaction with actin filaments, as well as functioning independently or in cooperation with APC to down-regulate beta-catenin signaling.
The Wnt/beta-catenin/Tcf and IkappaB/NF-kappaB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/beta-catenin signaling ...occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear beta-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IkappaB kinase complex (IKK) that phosphorylates IkappaB contains IKKalpha, IKKbeta, and IKKgamma. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/beta-catenin and IkappaB pathways in mitogenic signaling. Mitogenic induction of G(1)-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1(-/-) cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IkappaB/IKKalpha or beta-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKalpha. In IKKalpha(-/-) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKalpha restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKalpha(-/-) cells, beta-catenin phosphorylation was decreased and purified IKKalpha was sufficient for phosphorylation of beta-catenin through its N-terminus in vitro. Because IKKalpha but not IKKbeta induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKalpha and IKKbeta may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.
The wnt signaling pathway is involved in development, cell proliferation, cell differentiation, and cell motility. The tumor suppressor adenomatous polyposis coli (APC) and the oncogene beta-catenin, ...components of the wnt pathway, are commonly associated with a variety of cancers including colon, breast, ovarian, and melanoma. Upon wnt signaling, beta-catenin activates transcription of wnt target genes through interaction with Tcf/LEF transcription factors. In the absence of wnt signaling, beta-catenin is normally phosphorylated and targeted for degradation by a complex composed of APC, axin, and GSK3. Mutations in APC or beta-catenin lead to unregulated beta-catenin activation and ultimately cancer; therefore, it is important to study the mechanism of beta-catenin regulation. We identified a new human APC homologue, APC2, which is very similar in structure to APC. APC2 is localized to a region on chromosome 19p13.3 lost in a variety of cancers. An APC2 allelic imbalance was found in 19 of 20 sporadic ovarian tumors screened by FISH analysis suggesting APC2 could be a potential tumor suppressor gene. In the cell, APC2 localizes with the Golgi apparatus and actin filaments as well as the leading edge of the membrane. Based on recent APC studies, these results suggest that APC2 may function in cellular transport and cell motility. Like APC, APC2 can also down-regulate beta-catenin signaling activity. In the second part of this work, I provide evidence that IKK, the kinase complex previously thought to be responsible for only NF-kappaB activation, directly phosphorylates and down-regulates beta-catenin signaling. These results suggest that the wnt and NF-kappaB signaling pathways may overlap or “cross-talk”. The results presented in this dissertation not only increase our knowledge of beta-catenin regulation but also greatly increase the complexity of signaling pathways that regulate cell processes such as cell growth, cell motility, and inflammation.
Adverse experiences in childhood and adolescence, defined as subjectively perceived threats to the safety or security of the child’s bodily integrity, family, or social structures, are known to be ...associated with cardiometabolic outcomes over the life course into adulthood. This American Heart Association scientific statement reviews the scientific literature on the influence of childhood adversity on cardiometabolic outcomes that constitute the greatest public health burden in the United States, including obesity, hypertension, type 2 diabetes mellitus, and cardiovascular disease. This statement also conceptually outlines pathways linking adversity to cardiometabolic health, identifies evidence gaps, and provides suggestions for future research to inform practice and policy. We note that, despite a lack of objective agreement on what subjectively qualifies as exposure to childhood adversity and a dearth of prospective studies, substantial evidence documents an association between childhood adversity and cardiometabolic outcomes across the life course. Future studies that focus on mechanisms, resiliency, and vulnerability factors would further strengthen the evidence and provide much-needed information on targets for effective interventions. Given that childhood adversities affect cardiometabolic health and multiple health domains across the life course, interventions that ameliorate these initial upstream exposures may be more appropriate than interventions remediating downstream cardiovascular disease risk factor effects later in life.
Background
Patients with heart failure with preserved ejection fraction (HFpEF) exhibit macro‐ and microvascular dysfunction in both the upper and lower limbs that may be mediated by a decline in ...nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a vital cofactor for NO synthase (NOS) activity, the principal enzyme for NO production. BH4 insufficiency contributes to NOS uncoupling, which promotes cellular oxidative stress and limits NO production. While evidence supports the efficacy of BH4 supplementation to reverse NOS uncoupling in other patient populations, the utility of this intervention to restore vascular health has not been examined in HFpEF. We tested the hypothesis that short‐term BH4 supplementation would improve peripheral vascular function in patients with HFpEF.
Methods
Five patients with HFpEF (3F/2M; 72±8 years; 31.7±6.1 kg/m2) participated in a randomized, double‐blind crossover study, having consumed either BH4 (Sapropterin, 10 mg/kg) or placebo for 10 days, separated by a 14‐day washout period. Peripheral vascular function was assessed via flow‐mediated dilation (FMD; an index of macrovascular function) and reactive hyperemia (RH, an index of microvascular function) in both the arm (brachial artery, BA) and leg (popliteal artery, PA) at the beginning (pre) and end (post) of each treatment period.
Results
There were no baseline hemodynamic differences between trials (p>0.05). BA FMD was unchanged following either trial (pre vs. post; BH4: 3.2±2.5% vs. 4.0±1.9%, Δ 0.8±1.4%; Placebo: 2.9±1.9% vs. 2.2±2.2%, Δ ‐0.7±1.1%; p>0.05). Likewise, BA RH was unchanged following either trial (pre vs. post; BH4: 399±206 ml vs. 387±161 ml; Placebo: 242±126 ml vs. 174±149 ml; p>0.05). In contrast, PA FMD improved following the BH4 trial, but was unchanged in the placebo trial (pre vs. post; BH4: 1.5±1.2% vs. 2.5±0.8%; Placebo: 1.6±1.1% vs. 1.3±1.3%; p=0.03). Changes in %FMD for the PA were greater in BH4 compared to placebo (∆ values: 1.0±1.0% vs. ‐0.4±0.4%; p=0.03). No improvements were observed for PA RH (pre vs. post; BH4: 533±257 ml vs. 561±191 ml; Placebo: 682±284 ml vs. 656±107 ml; p>0.05).
Conclusion
These findings identify a potential for short‐term BH4 supplementation to improve lower limb macrovascular function in patients with HFpEF. This apparent vascular plasticity suggests that drugs targeting discreet points in the NO pathway may be efficacious in mitigating the disease‐related decline in vascular health in this patient group.
Abstract
Study Objectives
Post-traumatic stress disorder (PTSD) and rapid eye movement (REM) sleep behavior disorder (RBD) share some common features including prominent nightmares and sleep ...disturbances. We aimed to comparatively analyze REM sleep without atonia (RSWA) between patients with chronic PTSD with and without dream enactment behavior (DEB), isolated RBD (iRBD), and controls.
Methods
In this retrospective study, we comparatively analyzed 18 PTSD with DEB (PTSD+DEB), 18 PTSD without DEB, 15 iRBD, and 51 controls matched for age and sex. We reviewed medical records to determine PTSD clinical features and quantitatively analyzed RSWA. We used nonparametric analyses to compare clinical and polysomnographic features.
Results
PTSD patients, both with and without DEB, had significantly higher RSWA than controls (all p < .025, excepting submentalis phasic duration in PTSD+DEB). Most RSWA measures were also higher in PTSD+DEB than in PTSD without DEB patients (all p < .025).
Conclusions
PTSD patients have higher RSWA than controls, whether DEB is present or not, indicating that REM sleep atonia control is abnormal in chronic PTSD. Further prospective studies are needed to determine whether neurodegenerative risk and disease markers similar to RBD might occur in PTSD patients.
Through the voices of both faculty and student authors, we discuss the intentional integration of neurodiversity in an undergraduate, community geography research program. This exploratory case study ...takes conversations about diversity, equity, and inclusion from theory to practice presenting the development of an inclusive learning community through the lens of education and geoscience education frameworks. Through multiple perspectives advocating for systemic change for inclusive community geography, this paper presents actionable recommendations others in geography can draw from in their own efforts to broaden participation within geography field programs.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Devise-related infections after deep brain stimulator implantation are not uncommon. However, infections due to mycobacteria have not been reported in the medical literature. We describe the first ...reported case of DBS infection due to a novel rapidly growing mycobacteria, most closely resembling
Mycobacterium goodii
, by rpoB gene sequencing.
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