Donald Gullberg

University of Bergen, Bergen, Hordaland, Norway

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Publications (130)581.95 Total impact

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    ABSTRACT: Cell responses to the extracellular matrix depend on specific signaling events. These are important from early development, through differentiation and tissue homeostasis, immune surveillance and disease pathogenesis. Signaling not only regulates cell adhesion cytoskeletal organisation and motility, but also provides survival and proliferation cues. The major classes of cell surface receptors for matrix macromolecules are the integrins, discoidin domain receptors and transmembrane proteoglycans such as syndecans and CD44. Cells respond not only to specific ligands, such as collagen, fibronectin or basement membrane glycoproteins, but also in terms of matrix rigidity. This can regulate the release and subsequent biological activity of matrix-bound growth factors, for example transforming growth factor-β. In the environment of tumours, there may be changes in cell populations and their receptor profiles as well as matrix constitution and protein cross-linking. Here we summarize roles of the three major matrix receptor types, with emphasis on how they function in tumour progression.
    No preview · Article · Oct 2015 · Advanced drug delivery reviews
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    R Navab · D Strumpf · C To · E Pasko · K S Kim · C J Park · J Hai · J Liu · J Jonkman · M Barczyk · [...] · C Ng · N Radulovich · C-Q Zhu · M Pintilie · D Wang · A Lu · I Jurisica · G C Walker · D Gullberg · M-S Tsao ·
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    ABSTRACT: Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11(-/-)) mice was significantly impeded, as compared with wild-type (α11(+/+)) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11(-/-) and α11(+/+) mice showed significant reduction in the metastatic potential of these cells in the α11(-/-) mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11β1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.Oncogene advance online publication, 6 July 2015; doi:10.1038/onc.2015.254.
    Full-text · Article · Jul 2015 · Oncogene
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    ABSTRACT: The adhesion of cardiac fibroblasts to the glycated collagen interstitium in diabetics is associated with de novo expression of the α11 integrin, myofibroblast formation and cardiac fibrosis. We examined how methylglyoxal-glycated collagen regulates α11 integrin expression. In cardiac fibroblasts plated on glycated collagen but not glycated fibronectin, there was markedly increased α11 integrin and α-smooth muscle actin expression. Compared with native collagen, binding of purified α11β1 integrin to glycated collagen was reduced by >4-fold, which was consistent with reduced fibroblast attachment to glycated collagen. Glycated collagen strongly enhanced the expression of TGF-β2 but not TGF-β1 or TGF-β3. The increased expression of TGF-β2 was inhibited by triple helical collagen peptides that mimic the α11β1 integrin binding site on type I collagen. In cardiac fibroblasts transfected with α;11 integrin luciferase promoter constructs, glycated collagen activated the α11 integrin promoter. Analysis of α11 integrin promoter truncation mutants showed a novel Smad2/3 binding site located between -809 and -1300 nt that was required for promoter activation. We conclude that glycated collagen in the cardiac interstitium triggers an autocrine TGF-β2 signalling pathway that stimulates α11 integrin expression through Smad2/3 binding elements in the α11 integrin promoter, which is important for myofibroblast formation and fibrosis. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Feb 2015 · Journal of Cellular Physiology
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    ABSTRACT: Previous wound healing studies have failed to define a role for either α1β1 or α2β1 integrin in fibroblast-mediated wound contraction, suggesting the involvement of another collagen receptor in this process. Our previous work demonstrated that the integrin subunit α11 is highly induced during wound healing both at the mRNA and protein level, prompting us to investigate and dissect the role of the integrin α11β1 during this process. Therefore we used mice with a global ablation of either α2 or α11 or both integrin subunits and investigated the repair of excisional wounds. Analyses of wounds demonstrated that α11β1 deficiency results in reduced granulation tissue formation and impaired wound contraction, independently of the presence of α2β1. Our combined in vivo and in vitro data further demonstrate that dermal fibroblasts lacking α11β1 are unable to efficiently convert to myofibroblasts, resulting in scar tissue with compromised tensile strength. Moreover, we suggest that the reduced stability of the scar is a consequence of poor collagen remodeling in α11(-/-) wounds associated with defective TGF-β-dependent JNK signaling.Journal of Investigative Dermatology accepted article preview online, 29 January 2015. doi:10.1038/jid.2015.24.
    No preview · Article · Jan 2015 · Journal of Investigative Dermatology
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    ABSTRACT: Laminins (LM), basement membrane molecules and mediators of epithelial-stromal communication, are crucial in tissue homeostasis. Inflammatory Bowel Diseases (IBD) are multifactorial pathologies where the microenvironment and in particular LM play an important yet poorly understood role in tissue maintenance, and in cancer progression which represents an inherent risk of IBD. Here we showed first that in human IBD colonic samples and in murine colitis the LMα1 and LMα5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMα1 expression at the promoter level by ChIP analysis and this was confirmed by knockdown in cell transfection experiments. To mimic the human disease, we induced colitis and colitis-associated cancer by chemical treatment (DSS) combined or not with a carcinogen (AOM) in transgenic mice overexpressing LMα1 or LMα5 specifically in the intestine. We demonstrated that high LMα1 or LMα5 expression decreased susceptibility towards experimentally DSS-induced colon inflammation as assessed by histological scoring and decrease of pro-inflammatory cytokines. Yet in a pro-oncogenic context, we showed that LM would favor tumorigenesis as revealed by enhanced tumor lesion formation in both LM transgenic mice. Altogether, our results showed that nuclear p53 and associated overexpression of LMα1 and LMα5 protect tissue from inflammation. But in a mutation setting, the same LM molecules favor progression of IBD into colitis-associated cancer. Our transgenic mice represent attractive new models to acquire knowledge about the paradoxical effect of LM that mediate either tissue reparation or cancer according to the microenvironment. In the early phases of IBD, reinforcing basement membrane stability/organization could be a promising therapeutic approach.
    Full-text · Article · Oct 2014 · PLoS ONE

  • No preview · Article · Sep 2014 · Wound Repair and Regeneration
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    Cédric Zeltz · Donald Gullberg
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    ABSTRACT: Protein post-translational modifications like glycation, carbamylation and citrullination increase the functional diversity of the proteome but in disease situations might do more harm than good. Post-translational modifications of ECM proteins are thus appearing as mechanisms, which contribute to tissue dysfunction in chronic kidney disease, in diabetes and in various inflammatory diseases. In chronic renal failure, carbamylation could lead to kidney fibrosis. In diabetes, high glucose levels leads to non-enzymatic glycation and cross-linking of collagens, which contribute to tissue stiffening with consequences for cardiovascular and renal functions. In inflammatory diseases, citrullination deiminates arginine residues with possible consequences for integrin-mediated cell adhesion to RGD- and GFOGER sequences in ECM proteins. Citrullination of fibronectin was in one study shown to affect cell adhesion in a mechanism independent of RGD, but instead suggested to affect the heparin-binding site of fibronectin. In a recent publication citrullination of GFOGER sequences in collagen II was demonstrated to selectively affect α10β1 and α11β1 integrin-mediated cell adhesion to collagen II, with consequences for synovial fibroblast and stem cell adhesion and migration. The implications of citrullination affecting integrin binding in disease opens up a new area of study and might have implications for the pathogenesis of inflammatory diseases like rheumatoid arthritis and periodontitis.
    Preview · Article · Aug 2014 · Matrix Biology
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    ABSTRACT: We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+) or with a deletion (α11-/-) in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.
    Full-text · Article · Jul 2014 · PLoS ONE
  • Cédric Zeltz · Ning Lu · Donald Gullberg
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    ABSTRACT: Integrin α11 is the last addition to the vertebrate integrin family. In this chapter we will summarize some basic facts about this integrin and update with information that has been gained in the last decade. Integrin α11β1 is a major collagen receptor on a subset of fibroblasts. Extensive characterization of the expression pattern in developing mouse embryos has demonstrated expression restricted to subsets of fibroblasts and a transient expression in odontoblasts, but comprehensive characterization of corresponding expression in adult tissues is still lacking. Mice lacking integrin α11 are dwarfed, primarily due to defective incisor eruption defect, which can be traced back to need for α11 on periodontal ligament fibroblasts during incisor eruption. Separate studies have suggested reduced levels of IGF-1 in mice lacking α11. Analysis of lung cancer has identified α11β1 as a functional important collagen receptor on carcinoma associated fibroblasts (CAFs) and a number of disease models are awaiting analysis to see the importance of this collagen receptor in pathological models.
    No preview · Article · Jul 2014 · Advances in Experimental Medicine and Biology
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    ABSTRACT: Mechanical loading of tendon cells results in an upregulation of mechanotransduction signaling pathways, cell-matrix adhesion and collagen synthesis, but whether unloading removes these responses is unclear. We investigated the response to tension release, with regard to matrix proteins, pro-inflammatory mediators and tendon phenotypic specific molecules, in an in vitro model where tendon-like tissue was engineered from human tendon cells. Tissue sampling was performed 1, 2, 4 and 6 days after surgical de-tensioning of the tendon construct. When tensile stimulus was removed, integrin type collagen receptors showed a contrasting response with a clear drop in integrin subunit α11 mRNA and protein expression, and an increase in α2 integrin mRNA and protein levels. Further, specific markers for tendon cell differentiation declined and normal tendon architecture was disturbed, whereas pro-inflammatory molecules were upregulated. Stimulation with the cytokine TGF-β1 had distinct effects on some tendon-related genes in both tensioned and de-tensioned tissue. These findings indicate an important role of mechanical loading for cellular and matrix responses in tendon, including that loss of tension leads to a decrease in phenotypical markers for tendon, while expression of pro-inflammatory mediators is induced.
    Full-text · Article · Jan 2014 · PLoS ONE
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    ABSTRACT: Collagen XXII, a FACIT (fibril associated collagen with interrupted triple helices) collagen, is expressed at the myotendinous junction and the articular surface of joint cartilage. Cellular receptors like collagen binding integrins are known to bind collagens with distinct binding motifs following the sequence GXOGER. Here, we present the sequences GLQGER and GFKGER as novel binding motifs between collagen XXII and collagen binding integrins, especially α2β1 integrin. Solid phase assays and surface plasmon resonance spectroscopy revealed a direct interaction between α2β1 integrin and the motif GFKGER. In addition, immunohistochemical analysis demonstrated partial co-localization of collagen XXII, α2β1 integrin and α11β1 integrin at the myotendinous junction. Furthermore, computational modeling of the motifs GLQGER and GFKGER showed perfect fitting of the sequences into the binding pocket of collagen binding integrins. Taken together, we could demonstrate that collagen XXII interacts with collagen binding integrins via the new motifs GLQGER and GFKGER.
    No preview · Article · Jan 2014 · Biochemical Journal
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    Cédric Zeltz · Joseph Orgel · Donald Gullberg
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    ABSTRACT: Background: Despite detailed knowledge about the structure and signaling properties of individual collagen receptors, much remains to be learned about how these receptors participate in linking cells to fibrillar collagen matrices in tissues. In addition to collagen-binding integrins, a group of proteins with affinity both for fibrillar collagens and integrins link these two protein families together. We have introduced the name COLINBRI (COLlagen INtegrin BRIdging) for this set of molecules. Whereas collagens are the major building blocks in tissues and defects in these structural proteins have severe consequences for tissue integrity, the mild phenotypes of the integrin type of collagen receptors have raised questions about their importance in tissue biology and pathology. Scope of review: We will discuss the two types of cell linkages to fibrillar collagen (direct- versus indirect COLINBRI-mediated) and discuss how the parallel existence of direct and indirect linkages to collagens may ensure tissue integrity. Major conclusions: The observed mild phenotypes of mice deficient in collagen-binding integrins and the relatively restricted availability of integrin-binding sequences in mature fibrillar collagen matrices support the existence of indirect collagen-binding mechanisms in parallel with direct collagen binding in vivo. General significance: A continued focus on understanding the molecular details of cell adhesion mechanisms to collagens will be important and will benefit our understanding of diseases like tissue- and tumor fibrosis where collagen dynamics are disturbed. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
    Full-text · Article · Dec 2013 · Biochimica et Biophysica Acta
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    Malgorzata Barczyk · Anne Isine Bolstad · Donald Gullberg
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    ABSTRACT: The periodontal ligament is the tissue that connects teeth to bone. The periodontal ligament is a fascinating tissue from a cell biologist's point of view, and because of its special properties and stem-cell content it has also come into the limelight in emerging fields of regenerative medicine. An increased range of genetically modified mouse models offer new tools for studying molecular mechanisms of tooth development. However, owing to species-specific organization of the tooth apparatus, the use of genetic animal models to study the role of the periodontal ligament in normal human tooth physiology and tooth pathology is challenging.
    Full-text · Article · Oct 2013 · Periodontology 2000
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    ABSTRACT: Objective: The study was to investigate whether specific molecules expressed by activated cancer-associated fibroblasts (e.g. α-SMA (ACTA2) and integrin α11 (ITGA11)) can be used as prognostic markers for oral squamous cell carcinoma (OSCC) patients. Method: Fresh frozen (FF), formalin fixed paraffin embedded (FFPE) samples from healthy volunteers (n=10), patients with oral lichen planus (n=21), and OSCC (n=81) and clinical data were obtained with informed consent after approval from Regional Medical Ethical Committee. Samples were stained with monoclonal antibody for α-SMA (Thermo Scientific) and polyclonal antibody for integrin α11 (Velling, T. et al. JBC 1999) using En-Vision kit (DAKO). The staining for integrin α11 could not be optimized for FFPE material that contained also the tumor front. Data was analyzed using SPSS. Result: For frozen material, 81% of primary OSCCs were positive for α-SMA and 87% for integrin α11 in fibroblasts of tumor stroma in tumor center. No correlation was found between α-SMA or integrin α11 in frozen sections (tumor center only) and patient survival. For FFPE material, 94.23% of primary OSCCs, all metastases and recurrences were positive for α-SMA fibroblasts. Correlation between presence of α-SMA positive fibroblasts at tumor front, but not in tumor center with patient survival was found. Kaplan-Mayer survival analysis showed that patients with α-SMA positive fibroblasts in network arrangement (α-SMA rich) had significantly poorer prognosis compared to those with spindle shaped α-SMA-positive fibroblasts in tumor stroma (α-SMA poor). Conclusion: On FF samples correlation was found between α-SMA and integrin α11 staining. On FFPE samples presence of α-SMA positive fibroblasts at tumor front in a network pattern had prognostic value for survival of OSCC patients with carcinomas in other locations than tongue. In addition, we showed the critical importance of assessing tumor front when evaluating the potential of various molecules as prognostic biomarkers in OSCC.
    No preview · Conference Paper · Sep 2013
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    ABSTRACT: We have previously determined that integrin α11β1 is required on mouse periodontal ligament (PDL) fibroblasts to generate the force needed for incisor eruption. As part of the phenotype of α11(-/-) mice, the incisor PDL (iPDL) is thickened, due to disturbed matrix remodeling. To determine the molecular mechanism behind the disturbed matrix dynamics in the PDL we crossed α11(-/-) mice with the Immortomouse and isolated immortalized iPDL cells. Microarray analysis of iPDL cells cultured inside a 3D collagen gel demonstrated downregulated expression of a number of genes in α11-deficient iPDL cells, including matrix metalloproteinase-13 (MMP-13) and cathepsin K. α11(-/-) iPDL cells in vitro displayed disturbed interactions with collagen I during contraction of attached and floating collagen lattices and furthermore displayed reduced MMP-13 protein expression levels. The MMP-13 specific inhibitor WAY 170523 and the Cathepsin K Inhibitor II both blocked part of the α11 integrin-mediated collagen remodeling. In summary, our data demonstrate that in iPDL fibroblasts the mechanical strain generated by α11β1 integrin regulates molecules involved in collagen matrix dynamics. The positive regulation of α11β1-dependent matrix remodeling, involving MMP-13 and cathepsin K, might also occur in other types of fibroblasts and be an important regulatory mechanism for coordinated extracellular and intracellular collagen turnover in tissue homeostasis. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
    No preview · Article · May 2013 · Journal of Cellular Physiology
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    ABSTRACT: Here we describe a NOD/Scid mouse strain expressing the dsRed transgene. The strain is maintained by inbreeding of homozygous dsRed NOD/Scid siblings, and expresses red fluorescence from various organs. The model allows engraftment of human tumor tissue, and engrafted tumors were separated into stromal and malignant cell compartments. Furthermore, we compared tumor-associated and normal fibroblast for expression of fibroblast-associated markers, and identified a marker panel that was upregulated in the tumor-associated fibroblasts. In conclusion, we propose that this model may be used in a variety of studies of tumor progression and to elucidate the role of the tumor microenvironment.
    No preview · Article · Mar 2013 · Cancer Investigation

  • No preview · Article · Sep 2012 · The Canadian journal of cardiology
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    ABSTRACT: Diabetic cardiomyopathy is characterized by the production of a disorganized fibrotic matrix in the absence of coronary atherosclerosis and hypertension. We examined whether adhesion of cardiac fibroblasts to glycated collagens mediates the differentiation of pro-fibrotic myofibroblasts, which may contribute to cardiac fibrosis. By microarray, we found that methylglyoxal-treated collagen selectively enhanced α11 integrin expression in human cardiac fibroblasts, while levels of other collagen-binding integrins (α1, α2, and α10) were unchanged. Similar increases in α11 integrin mRNA and protein expression were observed in cardiac fibroblasts from streptozotocin (STZ)-treated Sprague-Dawley rats. In human cardiac fibroblasts plated on methyglyoxal-treated collagen and in cardiac fibroblasts from diabetic rats, transforming growth factor (TGF)-β2 but not TGF-β1 or TGF-β3 was increased compared with controls. Knock-down of α11 integrin and TGF-β receptors with small-interfering RNA blocked the increased expression of TGF-β2, α-smooth muscle actin (α-SMA), and α11 integrin that were induced in cells plated on methylglyoxal-treated collagen. Further, inhibition of Smad3 signalling blocked methylglyoxal-collagen up-regulation of α11 integrin and α-SMA expression. Rats with STZ-induced diabetes exhibited increased phosphorylation of Smad3 in cardiac tissues compared with control rats. Interactions between α11 integrins and the Smad-dependent TGF-β2 signalling may contribute to the formation of pro-fibrotic myofibroblasts and the development of a fibrotic interstitium in diabetic cardiomyopathy.
    No preview · Article · Aug 2012 · Cardiovascular Research
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    ABSTRACT: Stromal fibroblasts are important determinants of tumor cell behavior. They act to condition the tumor microenvironment, influence tumor growth, support tumor angiogenesis and affect tumor metastasis. Heparan sulfate proteoglycans, present both on tumor and stromal cells, interact with a large number of ligands including growth factors, their receptors, and structural components of the extracellular matrix. Being ubiquitously expressed in the tumor microenvironment heparan sulfate proteoglycans are candidates for playing central roles in tumor-stroma interactions. The objective of this work was to investigate the role of heparan sulfate expressed by stromal fibroblasts in modulating the growth of tumor cells and in controlling the interstitial fluid pressure in a 3-D model.
    Full-text · Article · Jul 2012 · PLoS ONE
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    ABSTRACT: Integrins are well characterized cell surface receptors for extracellular matrix proteins. Mapping integrin-binding sites within the fibrillar collagens identified GFOGER as a high affinity site recognized by α2β1, but with lower affinity for α1β1. Here, to identify specific ligands for α1β1, we examined binding of the recombinant human α1 I domain, the rat pheochromocytoma cell line (PC12), and the rat glioma Rugli cell line to our collagen Toolkit II and III peptides using solid-phase and real-time label-free adhesion assays. We observed Mg(2+)-dependent binding of the α1 I domain to the peptides in the following rank order: III-7 (GLOGEN), II-28 (GFOGER), II-7 and II-8 (GLOGER), II-18 (GAOGER), III-4 (GROGER). PC12 cells showed a similar profile. Using antibody blockade, we confirmed that binding of PC12 cells to peptide III-7 was mediated by integrin α1β1. We also identified a new α1β1-binding activity within peptide II-27. The sequence GVOGEA bound weakly to PC12 cells and strongly to activated Rugli cells or to an activated α1 I domain, but not to the α2 I domain or to C2C12 cells expressing α2β1 or α11β1. Thus, GVOGEA is specific for α1β1. Although recognized by both α2β1 and α11β1, GLOGEN is a better ligand for α1β1 compared with GFOGER. Finally, using biosensor assays, we show that although GLOGEN is able to compete for the α1 I domain from collagen IV (IC(50) ∼3 μm), GFOGER is much less potent (IC(50) ∼90 μm), as shown previously. These data confirm the selectivity of GFOGER for α2β1 and establish GLOGEN as a high affinity site for α1β1.
    Preview · Article · May 2012 · Journal of Biological Chemistry

Publication Stats

4k Citations
581.95 Total Impact Points


  • 2006-2015
    • University of Bergen
      • Department of Biomedicine
      Bergen, Hordaland, Norway
  • 2007
    • Academisch Centrum Tandheelkunde Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1986-2003
    • Uppsala University
      • • Department of Medical Biochemistry and Microbiology
      • • Department of Cell and Molecular Biology
      Uppsala, Uppsala, Sweden
  • 1996
    • Uppsala Monitoring Centre
      Uppsala, Uppsala, Sweden
  • 1994-1996
    • University of California, Los Angeles
      • Molecular Biology Institute
      Los Angeles, CA, United States