Medicine and Health Sciences Commons^™

Wnt Signaling Exerts An Antiproliferative Effect On Adult Cardiac Progenitor Cells Through Igfbp3., Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Frank Conyers, Michael Bauer, Annette Liao, Jian Guan, Dylan Crapps, Jung-Kyu Han, Hanhua Dong, Ahmad F Bayomy, Gabriel C Fine, Karen Westerman, Travis L Biechele, Randall T Moon, Thomas Force, Ronglih Liao

Center for Translational Medicine Faculty Papers

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.

OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.

METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical …

Systemic Adiponectin Malfunction As A Risk Factor For Cardiovascular Disease., Wayne Bond Lau, Ling Tao, Yajing Wang, Rong Li, Xin L Ma

Department of Emergency Medicine Faculty Papers

Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30 kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory …

Critical Role Of Pi3k/Akt/Gsk3Β In Motoneuron Specification From Human Neural Stem Cells In Response To Fgf2 And Egf, Luis Ojeda, Junling Gao, Kristopher G. Hooten, Enyin Wang, Jason R. Thonhoff, Tiffany J. Dunn, Tianyan Gao, Ping Wu

Markey Cancer Center Faculty Publications

Fibroblast growth factor (FGF) and epidermal growth factor (EGF) are critical for the development of the nervous system. We previously discovered that FGF2 and EGF had opposite effects on motor neuron differentiation from human fetal neural stem cells (hNSCs), but the underlying mechanisms remain unclear. Here, we show that FGF2 and EGF differentially affect the temporal patterns of Akt and glycogen synthase kinase 3 beta (GSK3β) activation. High levels of phosphatidylinositol 3-kinase (PI3K)/Akt activation accompanied with GSK3β inactivation result in reduction of the motor neuron transcription factor HB9. Inhibition of PI3K/Akt by chemical inhibitors or RNA interference or overexpression of …

Tlr4 Mutation Reduces Microglial Activation, Increases Aβ Deposits And Exacerbates Cognitive Deficits In A Mouse Model Of Alzheimer's Disease, Min Song, Jingji Jin, Jinghong Kou, Abhinandan Pattanayak, Jamaal Rehman, Hong-Duck Kim, Ken-Ichiro Fukuchi

NYMC Faculty Publications

BACKGROUND: Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it …

Protein Kinase Cδ And C-Abl Kinase Are Required For Transforming Growth Factor Β Induction Of Endothelial-Mesenchymal Transition In Vitro., Zhaodong Li, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: The origin of the mesenchymal cells responsible for the intimal fibrosis in systemic sclerosis (SSc) has not been fully identified. The present study was undertaken to investigate whether subendothelial mesenchymal cells may emerge through transdifferentiation of endothelial cells (ECs) into myofibroblasts via endothelial-mesenchymal transition (EndoMT) in vitro and to explore the signaling pathways involved in this process.

METHODS: Primary mouse pulmonary ECs isolated by immunomagnetic methods with sequential anti-CD34 and anti-CD102 antibody selection were cultured in monolayers. Cell morphology and diacetylated low-density lipoprotein uptake assays confirmed their EC characteristics. The induction of EndoMT was assessed by determination of α-smooth …

Tgfb1 Disrupts The Angiogenic Potential Of Microvascular Endothelial Cells Of The Corpus Luteum., Dulce Maroni, John S. Davis

Journal Articles: Obstetrics & Gynecology

Cyclical formation and regression of the ovarian corpus luteum is required for reproduction. During luteal regression, the microvasculature of the corpus luteum is extensively disrupted. Prostaglandin F2α, a primary signal for luteal regression, induces the expression of transforming growth factor β1 (TGFB1) in the corpus luteum. This study determined the actions of TGFB1 on microvascular endothelial cells isolated from the bovine corpus luteum (CLENDO cells). We hypothesized that TGFB1 participates in the disruption of the microvasculature during luteal regression. TGFB1 activated the canonical SMAD signaling pathway in CLENDO cells. TGFB1 (1 ng/ml) significantly reduced both basal and fetal-calf-serum-stimulated DNA synthesis, …

Microglial P38Α Mapk Is A Key Regulator Of Proinflammatory Cytokine Up-Regulation Induced By Toll-Like Receptor (Tlr) Ligands Or Beta-Amyloid (Aβ), Adam D. Bachstetter, Bin Xing, Lucia De Almeida, Edgardo R. Dimayuga, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Overproduction of proinflammatory cytokines from activated microglia has been implicated as an important contributor to pathophysiology progression in both acute and chronic neurodegenerative diseases. Therefore, it is critical to elucidate intracellular signaling pathways that are significant contributors to cytokine overproduction in microglia exposed to specific stressors, especially pathways amenable to drug interventions. The serine/threonine protein kinase p38α MAPK is a key enzyme in the parallel and convergent intracellular signaling pathways involved in stressor-induced production of IL-1β and TNFα in peripheral tissues, and is a drug development target for peripheral inflammatory diseases. However, much less is known about the quantitative …

Sonic Hedgehog Dependent Phosphorylation By Ck1Α And Grk2 Is Required For Ciliary Accumulation And Activation Of Smoothened, Yongbin Chen, Noriaki Sasai, Guoqiang Ma, Tao Yue, Jianhang Jia, James Briscoe, Jin Jiang

Markey Cancer Center Faculty Publications

Hedgehog (Hh) signaling regulates embryonic development and adult tissue homeostasis through the GPCR-like protein Smoothened (Smo), but how vertebrate Smo is activated remains poorly understood. In Drosophila, Hh dependent phosphorylation activates Smo. Whether this is also the case in vertebrates is unclear, owing to the marked sequence divergence between vertebrate and Drosophila Smo (dSmo) and the involvement of primary cilia in vertebrate Hh signaling. Here we demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. We demonstrate that …

Lipid Phosphate Phosphatase 3 Enables Efficient Thymic Egress, Béatrice Bréart, Willy D. Ramos-Perez, Alejandra Mendoza, Abdelghaffar K. Salous, Michael Gobert, Yong Huang, Ralf H. Adams, Juan J. Lafaille, Diana Escalante-Alcalde, Andrew J. Morris, Susan R. Schwab

Gill Heart & Vascular Institute Faculty Publications

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for …

Inhibition Of Phosphorylated C-Met In Rhabdomyosarcoma Cell Lines By A Small Molecule Inhibitor Su11274., Jinxuan Hou, Jixin Dong, Lijun Sun, Liying Geng, J. Wang, Jialin C. Zheng, Yan Li, Julia A. Bridge, Steven H. Hinrichs, Shi-Jian Ding

Journal Articles: Pathology and Microbiology

BACKGROUND: c-Met is a receptor tyrosine kinase (RTK) that is over-expressed in a variety of cancers and involved in cell growth, invasion, metastasis and angiogenesis. In this study, we investigated the role of c-Met in rhabdomyosarcoma (RMS) using its small molecule inhibitor SU11274, which has been hypothesized to be a potential therapeutic target for RMS.

METHODS: The expression level of phosphorylated c-Met in RMS cell lines (RD, CW9019 and RH30) and tumor tissues was assessed by phospho-RTK array and immunohistochemistry, respectively. The inhibition effects of SU11274 on RMS cells were studied with regard to intracellular signaling, cell proliferation, cell cycle …

Myd88 Is Pivotal For Immune Recognition Of Citrobacter Koseri And Astrocyte Activation During Cns Infection., Shuliang Liu, Tammy Kielian

Journal Articles: Pathology and Microbiology

Citrobacter koseri (C. koseri) is a Gram-negative bacterium that can cause a highly aggressive form of neonatal meningitis, which often progresses to establish multi-focal brain abscesses. The roles of Toll-like receptor 4 (TLR4) and its signaling adaptor MyD88 during CNS C. koseri infection have not yet been examined, which is important since recent evidence indicates that innate immune responses are tailored towards specific pathogen classes. Here TLR4 WT (C3H/FeJ) and TLR4 mutant (C3H/HeJ) mice as well as MyD88 KO animals were infected intracerebrally with live C. koseri, resulting in meningitis and ventriculitis with accompanying brain abscess formation. MyD88 KO mice …

Potent Inhibition Of Heterotopic Ossification By Nuclear Retinoic Acid Receptor-Γ Agonists., Kengo Shimono, Wei-En Tung, Christine Macolino, Amber Hsu-Tsai Chi, Johanna H Didizian, Christina Mundy, Roshantha A Chandraratna, Yuji Mishina, Motomi Enomoto-Iwamoto, Maurizio Pacifici, Masahiro Iwamoto

Department of Orthopaedic Surgery Faculty Papers

Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γ agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had …

Vimentin Is A Novel Akt1 Target Mediating Motility And Invasion., Q-S Zhu, K Rosenblatt, K-L Huang, G Lahat, R Brobey, S Bolshakov, T Nguyen, Z Ding, R Belousov, K Bill, X Luo, A Lazar, Adam Dicker, Md, Phd, G B Mills, M-C Hung, D Lev

Department of Radiation Oncology Faculty Papers

The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth and metabolic-related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial prometastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT-driven function. By implication, study of AKT signaling should optimally be conducted in an appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), the aggressive malignancies of mesenchymal origin, is poor, reflecting our modest ability to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving …

Ouabain Stimulates A Na+/K+-Atpase-Mediated Sfk-Activated Signalling Pathway That Regulates Tight Junction Function In The Mouse Blastocyst., Holly Giannatselis, Michele Calder, Andrew J Watson

Obstetrics & Gynaecology Publications

The Na(+)/K(+)-ATPase plays a pivotal role during preimplantation development; it establishes a trans-epithelial ionic gradient that facilitates the formation of the fluid-filled blastocyst cavity, crucial for implantation and successful pregnancy. The Na(+)/K(+)-ATPase is also implicated in regulating tight junctions and cardiotonic steroid (CTS)-induced signal transduction via SRC. We investigated the expression of SRC family kinase (SFK) members, Src and Yes, during preimplantation development and determined whether SFK activity is required for blastocyst formation. Embryos were collected following super-ovulation of CD1 or MF1 female mice. RT-PCR was used to detect SFK mRNAs encoding Src and Yes throughout preimplantation development. SRC and …