Medical Cell Biology Commons^™

Cdk Inhibitors (P16/P19/P21) Induce Senescence And Autophagy In Cancer-Associated Fibroblasts, "Fueling" Tumor Growth Via Paracrine Interactions, Without An Increase In Neo-Angiogenesis., Claudia Capparelli, Barbara Chiavarina, Diana Whitaker-Menezes, Timothy G Pestell, Richard Pestell, James Hulit, Sebastiano Andò, Anthony Howell, Ubaldo E. Martinez-Outshoorn, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, …

Metabolic Remodeling Of The Tumor Microenvironment: Migration Stimulating Factor (Msf) Reprograms Myofibroblasts Toward Lactate Production, Fueling Anabolic Tumor Growth., Valentina Carito, Gloria Bonuccelli, Ubaldo E Martinez-Outschoorn, Diana Whitaker-Menezes, Maria Cristina Caroleo, Erika Cione, Anthony Howell, Richard G Pestell, Michael P. Lisanti, Federica Sotgia

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate …

Inflammation, Organomegaly, And Muscle Wasting Despite Hyperphagia In A Mouse Model Of Burn Cachexia., Felipe E Pedroso, Paul B Spalding, Michael C Cheung, Relin Yang, Juan C Gutierrez, Andrea Bonetto, Rui Zhan, Ho Lam Chan, Nicholas Namias, Leonidas G Koniaris, Teresa A Zimmers

Department of Cancer Biology Faculty Papers

BACKGROUND: Burn injury results in a chronic inflammatory, hypermetabolic, and hypercatabolic state persisting long after initial injury and wound healing. Burn survivors experience a profound and prolonged loss of lean body mass, fat mass, and bone mineral density, associated with significant morbidity and reduced quality of life. Understanding the mechanisms responsible is essential for developing therapies. A complete characterization of the pathophysiology of burn cachexia in a reproducible mouse model was lacking.

METHODS: Young adult (12-16 weeks of age) male C57BL/6J mice were given full thickness burns using heated brass plates or sham injury. Food and water intake, organ and …

Mini-Review: Decorin, A Guardian From The Matrix, Thomas Neill, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor-β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of …

Regulation Of Lipogenesis By Cyclin-Dependent Kinase 8-Mediated Control Of Srebp-1., Xiaoping Zhao, Daorong Feng, Qun Wang, Arian Abdulla, Xiao-Jun Xie, Jie Zhou, Yan Sun, Ellen S Yang, Lu-Ping Liu, Bhavapriya Vaitheesvaran, Lauren Bridges, Irwin J Kurland, Randy Strich, Jian-Quan Ni, Chenguang Wang, Johan Ericsson, Jeffrey E Pessin, Jun-Yuan Ji, Fajun Yang

Department of Cancer Biology Faculty Papers

Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein …

Two-Compartment Tumor Metabolism: Autophagy In The Tumor Microenvironment And Oxidative Mitochondrial Metabolism (Oxphos) In Cancer Cells., Ahmed F Salem, Diana Whitaker-Menezes, Zhao Lin, Ubaldo E. Martinez-Outshoorn, Herbert B Tanowitz, Mazhar Salim Al-Zoubi, Anthony Howell, Richard Pestell, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in tumor metabolism. In this model, autophagy and mitochondrial dysfunction in the tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high-energy "fuels" would then drive the anabolic growth of tumors, via autophagy resistance and oxidative mitochondrial metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: "two-compartment tumor metabolism." Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased …

Autophagy And Senescence In Cancer-Associated Fibroblasts Metabolically Supports Tumor Growth And Metastasis Via Glycolysis And Ketone Production., Claudia Capparelli, Carmela Guido, Diana Whitaker-Menezes, Phd, Gloria Bonuccelli, Renee Balliet, Timothy G Pestell, Allison F Goldberg, Richard Pestell, Anthony Howell, Sharon Sneddon, Ruth Birbe, Aristotelis Tsirigos, Ubaldo E. Martinez-Outshoorn, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTERT-BJ1) were stably transfected with autophagy genes (BNIP3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed …

Ctgf Drives Autophagy, Glycolysis And Senescence In Cancer-Associated Fibroblasts Via Hif1 Activation, Metabolically Promoting Tumor Growth., Claudia Capparelli, Diana Whitaker-Menezes, Carmela Guido, Renee Balliet, Timothy G Pestell, Anthony Howell, Sharon Sneddon, Richard Pestell, Ubaldo E. Martinez-Outshoorn, Michael P. Lisanti, Federica Sotgia

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Previous studies have demonstrated that loss of caveolin-1 (Cav-1) in stromal cells drives the activation of the TGF-β signaling, with increased transcription of TGF-β target genes, such as connective tissue growth factor (CTGF). In addition, loss of stromal Cav-1 results in the metabolic reprogramming of cancer-associated fibroblasts, with the induction of autophagy and glycolysis. However, it remains unknown if activation of the TGF-β / CTGF pathway regulates the metabolism of cancer-associated fibroblasts. Therefore, we investigated whether CTGF modulates metabolism in the tumor microenvironment. For this purpose, CTGF was overexpressed in normal human fibroblasts or MDA-MB-231 breast cancer cells. Overexpression of …

Proline-Rich Tyrosine Kinase 2 (Pyk2) Regulates Igf-I-Induced Cell Motility And Invasion Of Urothelial Carcinoma Cells, Marco Genua, Shi-Qiong Xu, Simone Buraschi, Stephen C. Peiper, Leonard G. Gomella, Antonio Belfiore, Renato V. Iozzo, Andrea Morrione

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in …

Genetic Ablation Of Cav1 Differentially Affects Melanoma Tumor Growth And Metastasis In Mice: Role Of Cav1 In Shh Heterotypic Signaling And Transendothelial Migration., Franco Capozza, Casey Trimmer, Remedios Castello-Cros, Sanjay Katiyar, Diana Whitaker-Menezes, Antonia Follenzi, Marco Crosariol, Gemma Llaverias, Federica Sotgia, Richard G Pestell, Michael P Lisanti

Department of Cancer Biology Faculty Papers

Both cell-autonomous and non-cell-autonomous factors contribute to tumor growth and metastasis of melanoma. The function of caveolin-1 (Cav1), a multifunctional scaffold protein known to modulate several biologic processes in both normal tissue and cancer, has been recently investigated in melanoma cancer cells, but its role in the melanoma microenvironment remains largely unexplored. Here, we show that orthotopic implantation of B16F10 melanoma cells in the skin of Cav1KO mice increases tumor growth, and co-injection of Cav1-deficient dermal fibroblasts with melanoma cells is sufficient to recapitulate the tumor phenotype observed in Cav1KO mice. Using indirect coculture experiments with fibroblasts and melanoma cells …

Genetic Polymorphism In A Vegf-Independent Angiogenesis Gene Angpt1 And Overall Survival Of Colorectal Cancer Patients After Surgical Resection, Jingyao Dai, Shaogui Wan, Feng Zhou, Ronald E. Myers, Xu Guo, Bingshan Li, Xiaoying Fu, Juan P. Palazzo, Kefeng Dou, Hushan Yang, Jinliang Xing

Kimmel Cancer Center Faculty Papers

Background

The VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). However, its implication in the clinical outcome of CRC has not been reported. This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients.

Methods

Seven single nucleotide polymorphisms (SNPs) in four important VEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4 and ENG) were genotyped in a Chinese population with 408 CRC patients.

Results

One SNP, rs1954727 in ANGPT1, was significantly associated with CRC overall survival. Compared to …

Essential Role Of Caveolin-3 In Adiponectin Signalsome Formation And Adiponectin Cardioprotection., Yajing Wang, Xiaoliang Wang, Jean-François Jasmin, Wayne Bond Lau, Rong Li, Yuexin Yuan, Wei Yi, Kurt Chuprun, Michael P. Lisanti, Walter J Koch, Erhe Gao, Xin-Liang Ma

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Adiponectin (APN) system malfunction is causatively related to increased cardiovascular morbidity/mortality in diabetic patients. The aim of the current study was to investigate molecular mechanisms responsible for APN transmembrane signaling and cardioprotection.

METHODS AND RESULTS: Compared with wild-type mice, caveolin-3 knockout (Cav-3KO) mice exhibited modestly increased myocardial ischemia/reperfusion injury (increased infarct size, apoptosis, and poorer cardiac function recovery; P

CONCLUSIONS: Taken together, these results demonstrated for the first time that Cav-3 plays an essential role in APN transmembrane signaling and APN anti-ischemic/cardioprotective actions.

Expression Of Stem Cell Marker Aldh1 In Cervical Intraepithelial Neoplasia, Ping Gong, Juan Palazzo, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusions:

Cervical dysplasia show positive staining for ALDH1 compared to normal cervical mucosa.

ALDH1 positive cells distribution parallels the dysplastic cells in cervical dysplasia.

CSC, as detected by ALDH1 expression, may play a role in the progression of cervical intraepithelial neoplasia and carcinogenesis.

Loss Of Retinoblastoma (Rb) Tumor Suppressor Expression In Breast Cancer Correlates With Better Response To Neoadjuvant Chemotherapy, Jeanne Mcfalls, Md, Jessica Kline, Ba, Gordon Schwartz, Md, Mba, Facs, Angieszka Witkiewicz, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusions:

Loss of RB tumor suppressor staining in pre-treatment breast cancer biopsies can be used prior to initiation of neoadjuvant chemotherapy to predict good tumor response. This association between RB loss and good neoadjuvant response holds regardless of ER status and across various chemotherapy regimens. Assessment of RB status in the pre-treatment biopsy could be useful clinical tool to define patients who are most likely to benefit from neoadjuvant chemotherapy.

P53 Expression In Oropharyngeal Squamous Cell Carcinoma In Increased In Hpv Positive Smokers, Madalina Tuluc, Voichita Bar-Ad, Zi-Xuan Wang, Joseph Curry

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background and Objectives

High risk HPV is associated with oropharyngeal SCC (OSCC) and is responsible for the increasing incidence of this cancer type among younger patients.

Patients with HPV positive oropharyngeal SCC have a better prognosis when compared with HPV negative, tobacco induced SCC.

HPV E6 inactivates p53 leading to low expression of p53; tobacco induced oropharyngeal SCC is characterized by p53 overexpression, resistance to treatment and poor prognosis. However, in many cases of HPV OSCC, there is a history of current or remote smoking, making this disease a multifactorial process. We expect that smoking will influence the level of …

The Metastasis Suppressor Kiss1 Lacks Antimetastatic Activity In The C8161.9 Xenograft Model Of Melanoma., Jean-Marc Navenot, Barry Evans, Shinya Oishi, Shohei Setsuda, Nobutaka Fujii, Stephen C Peiper

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS …

Aberrant Expression Of Cd56 On Granulocytes And Monocytes In Myeloproliferative Neoplasm And Myelodysplastic Syndrome, Ping Gong, Md, Fernanco Metrebian, Md, Alina Dulau-Florea, Md, Zi-Xuan Wang, Phd, Renu Bajaj, Phd, Stephen C Peiper, Jerald Z. Gong, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusions:

Aberrant CD56 expression on granulocytes is seen in all aubtypes MPN and high grade MDS. CD56 expression in MPN correlated with bone marrow morphology, BCR/ABL transcript, and bone marrow engraftment study following treatment. Identification of abnormal CD56+ granulocytes and monocytes is helpful in both the initial diagnosis and long-term follow up of patients with MPN and MDS.

P16/Rb Correlations In Oropharyngeal Squamous Cell Carcinoma (Oscc), Madalina Tuluc, Voichita Bar-Ad, David Cognetti

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The objective of this study is to explore the patterns of Rb expression in p16 positive and negative OSCC, in relation to patient's smoking history.

Cyclin D1 Induces Chromosomal Instability., Mathew C Casimiro, Richard Pestell

Department of Cancer Biology Faculty Papers

We developed mouse model systems to investigate the potential for cyclin D1 to induce CIN in vivo. In a mammary gland specific Tet-inducible model the acute expression profile regulated by cyclin D1 after 7 days was enriched in genes that rank highly with CIN. We also used a mammary gland targeted model (MMTV) to continuously express cyclin D1. The mice started to develop mammary gland tumors at 400 days and the tumor-free incidence was 40% in MMTV-cyclin D1. The gene expression profile of the tumors showed enrichment for the CIN signature. We next compared cyclin D1 expression and the highest …

Decorin-Mediated Inhibition Of Colorectal Cancer Growth And Migration Is Associated With E-Cadherin In Vitro And In Mice., Xiuli Bi, Nicole M Pohl, Zhibin Qian, George R Yang, Yuan Gou, Grace Guzman, Andre Kajdacsy-Balla, Renato V Iozzo, Wancai Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27(kip1) and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435-1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn(-/-) mice) and manipulated expression of decorin …

Decorin Antagonizes The Angiogenic Network: Concurrent Inhibition Of Met, Hypoxia Inducible Factor 1Α, Vascular Endothelial Growth Factor A, And Induction Of Thrombospondin-1 And Timp3, Thomas Neill, Hannah Painter, Simone Buraschi, Rick T. Owens, Michael P. Lisanti, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous …

Pressure-Overload-Induced Subcellular Relocalization/Oxidation Of Soluble Guanylyl Cyclase In The Heart Modulates Enzyme Stimulation., Emily J Tsai, Yuchuan Liu, Norimichi Koitabashi, Djahida Bedja, Thomas Danner, Jean-Francois Jasmin, Michael P Lisanti, Andreas Friebe, Eiki Takimoto, David A Kass

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

RATIONALE: Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) upon activation by nitric oxide (NO). Cardiac NO-sGC-cGMP signaling blunts cardiac stress responses, including pressure-overload-induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis.

OBJECTIVE: We tested the hypothesis that the sGC response to NO also declines with pressure-overload stress and assessed the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms.

METHODS AND RESULTS: C57BL/6 mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and dysfunction. NO-stimulated sGC activity was markedly depressed, whereas NO- and heme-independent sGC …

Orai1 Deficiency Leads To Heart Failure And Skeletal Myopathy In Zebrafish., Mirko Völkers, Nima Dolatabadi, Natalie Gude, Patrick Most, Mark A Sussman, David Hassel

Center for Translational Medicine Faculty Papers

Mutations in the store-operated Ca²⁺ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss …

Uterine Dysfunction In Biglycan And Decorin Deficient Mice Leads To Dystocia During Parturition., Zhiping Wu, Abraham W Aron, Elyse E Macksoud, Renato V Iozzo, Chi-Ming Hai, Beatrice E Lechner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, …

Enteric Alpha Defensins In Norm And Pathology., Nikolai A Lisitsyn, Yulia A Bukurova, Inna G Nikitina, George S Krasnov, Yuri Sykulev, Sergey F Beresten

Kimmel Cancer Center Faculty Papers

ABSTRACT: Microbes living in the mammalian gut exist in constant contact with immunity system that prevents infection and maintains homeostasis. Enteric alpha defensins play an important role in regulation of bacterial colonization of the gut, as well as in activation of pro- and anti-inflammatory responses of the adaptive immune system cells in lamina propria. This review summarizes currently available data on functions of mammalian enteric alpha defensins in the immune defense and changes in their secretion in intestinal inflammatory diseases and cancer.

Aleuria Aurantia Lectin (Aal)-Reactive Immunoglobulin G Rapidly Appears In Sera Of Animals Following Antigen Exposure., Songming Chen, Chen Lu, Hongbo Gu, Anand Mehta, Jianwei Li, Patrick B Romano, David Horn, D Craig Hooper, Carthene R Bazemore-Walker, Timothy Block

Department of Cancer Biology Faculty Papers

We have discovered an Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G (IgG) that naturally occurs in the circulation of rabbits and mice, following immune responses induced by various foreign antigens. AAL can specifically bind to fucose moieties on glycoproteins. However, most serum IgGs are poorly bound by AAL unless they are denatured or treated with glycosidase. In this study, using an immunogen-independent AAL-antibody microarray assay that we developed, we detected AAL-reactive IgG in the sera of all animals that had been immunized 1-2 weeks previously with various immunogens with and without adjuvants and developed immunogen-specific responses. All of these animals subsequently …

Aleuria Aurantia Lectin (Aal)-Reactive Immunoglobulin G Rapidly Appears In Sera Of Animals Following Antigen Exposure., Songming Chen, Chen Lu, Hongbo Gu, Anand Mehta, Jianwei Li, Patrick B Romano, David Horn, D Craig Hooper, Carthene R Bazemore-Walker, Timothy Block

Department of Cancer Biology Faculty Papers

We have discovered an Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G (IgG) that naturally occurs in the circulation of rabbits and mice, following immune responses induced by various foreign antigens. AAL can specifically bind to fucose moieties on glycoproteins. However, most serum IgGs are poorly bound by AAL unless they are denatured or treated with glycosidase. In this study, using an immunogen-independent AAL-antibody microarray assay that we developed, we detected AAL-reactive IgG in the sera of all animals that had been immunized 1-2 weeks previously with various immunogens with and without adjuvants and developed immunogen-specific responses. All of these animals subsequently …

Orphan Nuclear Receptor Nur77 Regulates Androgen Receptor Gene Expression In Mouse Ovary., Anyi Dai, Guijun Yan, Qinyuan He, Yue Jiang, Qun Zhang, Ting Fang, Lijun Ding, Jianxin Sun, Haixiang Sun, Yali Hu

Center for Translational Medicine Faculty Papers

The androgen receptor (AR) is a nuclear receptor that is expressed in growing follicles and involved in folliculogenesis and follicle growth. The orphan nuclear receptor, Nur77, also has an important role in steroid signaling and follicle maturation. We hypothesized that AR levels and androgen signaling through AR are regulated by Nur77 in the ovary. In the ovaries of Nur77 knockout mice (n = 5), real-time PCR results showed that the mRNA levels of AR and an androgen signaling target gene, Kitl, were decreased by 35% and 24%, respectively, relative to wild-type mice (n = 5), which suggested transcriptional regulation of …

Keratinocyte-Targeted Expression Of Human Laminin Γ2 Rescues Skin Blistering And Early Lethality Of Laminin Γ2 Deficient Mice., Tracy L Adair-Kirk, Gail L Griffin, Michelle J Meyer, Diane G Kelley, Jeffrey H Miner, Douglas R Keene, M Peter Marinkovich, J Michael Ruppert, Jouni Uitto, Robert M Senior

Department of Dermatology and Cutaneous Biology Faculty Papers

Laminin-332 is a heterotrimeric basement membrane component comprised of the α3, ß3, and γ2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early …

Administration Of Bone Marrow Derived Mesenchymal Stem Cells Into The Liver: Potential To Rescue Pseudoxanthoma Elasticum In A Mouse Model (Abcc6-/-)., Qiujie Jiang, Shunsuke Takahagi, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder caused by loss-of-function mutations in the ABCC6 gene which is primarily expressed in the liver. There is currently no effective treatment for PXE. In this study, we characterized bone marrow derived mesenchymal stem cells (MSCs) and evaluated their ability to contribute to liver regeneration, with the aim to rescue PXE phenotype. The MSCs, isolated from GFP-transgenic mice by magnetic cell sorting, were shown to have high potential for hepatic differentiation, with expression of Abcc6, in culture. These cells were transplanted into the livers of 4-week-old immunodeficient Abcc6⁻/⁻ mice by intrasplenic injection …