Publications by authors named "Rommel Advincula"

18 Publications

  • Page 1 of 1

Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation.

Nat Immunol 2020 04 16;21(4):422-433. Epub 2020 Mar 16.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

A20 is an anti-inflammatory protein that is strongly linked to human disease. Here, we find that mice expressing three distinct targeted mutations of A20's zinc finger 7 (ZF7) ubiquitin-binding motif uniformly developed digit arthritis with features common to psoriatic arthritis, while mice expressing point mutations in A20's OTU or ZF4 motifs did not exhibit this phenotype. Arthritis in A20 mice required T cells and MyD88, was exquisitely sensitive to tumor necrosis factor and interleukin-17A, and persisted in germ-free conditions. A20 cells exhibited prolonged IκB kinase activity that drove exaggerated transcription of late-phase nuclear factor-κB response genes in vitro and in prediseased mouse paws in vivo. In addition, mice expressing double-mutant A20 proteins in A20's ZF4 and ZF7 motifs died perinatally with multi-organ inflammation. Therefore, A20's ZF4 and ZF7 motifs synergistically prevent inflammatory disease in a non-catalytic manner.
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http://dx.doi.org/10.1038/s41590-020-0634-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195210PMC
April 2020

A20 in dendritic cells restrains intestinal anti-bacterial peptide expression and preserves commensal homeostasis.

PLoS One 2019 11;14(7):e0218999. Epub 2019 Jul 11.

Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America.

Microbial dysbiosis commonly occurs in patients with inflammatory bowel diseases (IBD). Exogenous causes of dysbiosis such as antibiotics and diet are well described, but host derived causes are understudied. A20 is a potent regulator of signals triggered by microbial pattern molecules, and A20 regulates susceptibility to intestinal inflammation in mice and in humans. We now report that mice lacking A20 expression in dendritic cells, A20FL/FL CD11c-Cre mice (or A20dDC mice), spontaneously develop colitogenic intestinal dysbiosis that is evident upon weaning and precedes the onset of colitis. Intestines from A20dDC mice express increased amounts of Reg3β and Reg3γ, but not Ang4. A20 deficient DCs promote gut microbiota perturbation in the absence of adaptive lymphocytes. Moreover, A20 deficient DCs directly induce expression of Reg3β and Reg3γ but not Ang 4 in normal intestinal epithelial cell enteroid cultures in the absence of other cell types. These findings reveal a pathophysiological pathway in which defective expression of an IBD susceptibility gene in DCs drives aberrant expression of anti-bacterial peptides and luminal dysbiosis that in turn confers host susceptibility to intestinal inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218999PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622485PMC
February 2020

A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival.

J Exp Med 2018 07 21;215(7):1839-1852. Epub 2018 Jun 21.

Department of Medicine, University of California, San Francisco, San Francisco, CA

A20 () and ABIN-1 () are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.
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http://dx.doi.org/10.1084/jem.20180198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028510PMC
July 2018

The Ubiquitin Binding Protein TAX1BP1 Mediates Autophagasome Induction and the Metabolic Transition of Activated T Cells.

Immunity 2017 03 14;46(3):405-420. Epub 2017 Mar 14.

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA. Electronic address:

During immune responses, naive T cells transition from small quiescent cells to rapidly cycling cells. We have found that T cells lacking TAX1BP1 exhibit delays in growth of cell size and cell cycling. TAX1BP1-deficient T cells exited G but stalled in S phase, due to both bioenergetic and biosynthetic defects. These defects were due to deficiencies in mTOR complex formation and activation. These mTOR defects in turn resulted from defective autophagy induction. TAX1BP1 binding of LC3 and GABARAP via its LC3-interacting region (LIR), but not its ubiquitin-binding domain, supported T cell proliferation. Supplementation of TAX1BP1-deficient T cells with metabolically active L-cysteine rescued mTOR activation and proliferation but not autophagy. These studies reveal that TAX1BP1 drives a specialized form of autophagy, providing critical amino acids that activate mTOR and enable the metabolic transition of activated T cells.
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http://dx.doi.org/10.1016/j.immuni.2017.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400745PMC
March 2017

The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis.

Nat Immunol 2015 Jun 4;16(6):618-27. Epub 2015 May 4.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

A20 is an anti-inflammatory protein linked to multiple human diseases; however, the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We found that A20-deficient T cells and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. Global deficiency in RIPK3 significantly restored the survival of A20-deficient mice. A20-deficient cells exhibited exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 underwent physiological ubiquitination at Lys5 (K5), and this ubiquitination event supported the formation of RIPK1-RIPK3 complexes. Both the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex required the catalytic cysteine of A20's deubiquitinating motif. Our studies link A20 and the ubiquitination of RIPK3 to necroptotic cell death and suggest additional mechanisms by which A20 might prevent inflammatory disease.
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http://dx.doi.org/10.1038/ni.3172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439357PMC
June 2015

A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity.

Immunity 2015 Jan;42(1):55-67

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NF-κB inhibitor A20 is a ubiquitin-modifying enzyme that might be critical in preventing human inflammatory diseases. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1β, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1β also co-immunoprecipitates with RIPK1, RIPK3, caspase-1, and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1β-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1β is a physiological ubiquitination site that supports processing. Our study reveals a mechanism by which A20 prevents inflammatory diseases.
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http://dx.doi.org/10.1016/j.immuni.2014.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302274PMC
January 2015

Cutting edge: ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells.

J Immunol 2013 Jul 19;191(2):535-9. Epub 2013 Jun 19.

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

Psoriasis is a chronic, inflammatory skin disease caused by a combination of environmental and genetic factors. The Tnip1 gene encodes A20 binding and inhibitor of NF-κB-1 (ABIN-1) protein and is strongly associated with susceptibility to psoriasis in humans. ABIN-1, a widely expressed ubiquitin-binding protein, restricts TNF- and TLR-induced signals. In this study, we report that mice lacking ABIN-1 specifically in dendritic cells (DCs), ABIN-1(fl) CD11c-Cre mice, exhibit perturbed immune homeostasis. ABIN-1-deficient DCs display exaggerated NF-κB and MAPK signaling and produce more IL-23 than do normal cells in response to TLR ligands. Challenge of ABIN-1(fl) CD11c-Cre mice with topical TLR7 ligand leads to greater numbers of Th17 and TCRγδ T cells and exacerbated development of psoriaform lesions. These phenotypes are reversed by DC-specific deletion of the TLR adaptor MyD88. These studies link ABIN-1 with IL-23 and IL-17, and they provide cellular and molecular mechanisms by which ABIN-1 regulates susceptibility to psoriasis.
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http://dx.doi.org/10.4049/jimmunol.1203335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702626PMC
July 2013

A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis.

PLoS One 2013 6;8(5):e62223. Epub 2013 May 6.

Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.

Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3), a ubiquitin-editing enzyme that restricts NFκB and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min)). While A20(FL/FL) villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL) villin-Cre APC(min/+) mice contain far greater numbers and larger colonic polyps than control APC(min) mice. We find that A20 binds to the β-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of β-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the β-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting β-catenin signaling and preventing colon tumorigenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645994PMC
December 2013

Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme.

Immunity 2013 May 18;38(5):896-905. Epub 2013 Apr 18.

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0451, USA.

A20 is an anti-inflammatory protein linked to multiple human autoimmune diseases and lymphomas. A20 possesses a deubiquitinating motif and a zinc finger, ZF4, that binds ubiquitin and supports its E3 ubiquitin ligase activity. To understand how these activities mediate A20's physiological functions, we generated two lines of gene-targeted mice, abrogating either A20's deubiquitinating activity (Tnfaip3(OTU) mice) or A20's ZF4 (Tnfaip3(ZF4) mice). Both Tnfaip3(OTU) and Tnfaip3(ZF4) mice exhibited increased responses to TNF and sensitivity to colitis. A20's C103 deubiquitinating motif restricted both K48- and K63-linked ubiquitination of receptor interacting protein 1 (RIP1). A20's ZF4 was required for recruiting A20 to ubiquitinated RIP1. A20(OTU) proteins and A20(ZF4) proteins complemented each other to regulate RIP1 ubiquitination and NFκB signaling normally in compound mutant Tnfaip3(OTU/ZF4) cells. This complementation involved homodimerization of A20 proteins, and we have defined an extensive dimerization interface in A20. These studies reveal how A20 proteins collaborate to restrict TNF signaling.
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http://dx.doi.org/10.1016/j.immuni.2013.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665706PMC
May 2013

Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis.

Nat Immunol 2011 Oct 23;12(12):1184-93. Epub 2011 Oct 23.

Department of Medicine, University of California at San Francisco, San Francisco, California, USA.

Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.
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http://dx.doi.org/10.1038/ni.2135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419270PMC
October 2011

The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity.

Immunity 2010 Aug 12;33(2):181-91. Epub 2010 Aug 12.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

A20 is a ubiquitin modifying enzyme that restricts NF-kappaB signals and protects cells against tumor necrosis factor (TNF)-induced programmed cell death. Given recent data linking A20 (TNFAIP3) with human B cell lymphomas and systemic lupus erythematosus (SLE), we have generated mice bearing a floxed allele of Tnfaip3 to interrogate A20's roles in regulating B cell functions. A20-deficient B cells are hyperresponsive to multiple stimuli and display exaggerated NF-kappaB responses to CD40-induced signals. Mice expressing absent or hypomorphic amounts of A20 in B cells possess elevated numbers of germinal center B cells, autoantibodies, and glomerular immunoglobulin deposits. A20-deficient B cells are resistant to Fas-mediated cell death, probably due to increased expression of NF-kappaB-dependent antiapoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, whereas A20 protects other cells from TNF-induced cell death. Our studies demonstrate how reduced A20 expression predisposes to autoimmunity.
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http://dx.doi.org/10.1016/j.immuni.2010.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931361PMC
August 2010

Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8+ T cell subsets.

Immunity 2009 Nov 12;31(5):811-22. Epub 2009 Nov 12.

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0451, USA.

Interleukin-15 receptor alpha (IL-15R alpha) is a pleiotropically expressed molecule that chaperones and trans-presents IL-15 to NK and T cells. To investigate whether IL-15R alpha presented by different cells perform distinct physiological functions, we have generated four lines of mice lacking IL-15R alpha in various cell types. We find that IL-15R alpha expression on macrophages but not dendritic cells (DCs) supports the early transition of antigen specific effector CD8(+) T cells to memory cells. After memory CD8(+) T cell differentiation, IL-15R alpha expression on DCs selectively supports central memory CD8(+) T cells, whereas IL-15R alpha expression on macrophages supports both central and effector memory CD8(+) T cells. By contrast, mice lacking IL-15R alpha on macrophages, DCs, or both, exhibit equivalent defects in NK cell homeostasis and activation. These studies define unique roles for macrophage expression of IL-15R alpha and show that NK cells rely upon distinct IL-15R alpha dependent IL-15 signals than memory CD8(+) T cells. Moreover, they demonstrate the diversity, specification, and geographic restriction of cytokine signals.
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http://dx.doi.org/10.1016/j.immuni.2009.09.017DOI Listing
November 2009

ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development.

Nature 2009 Feb 7;457(7231):906-9. Epub 2008 Dec 7.

Department of Medicine, University of California at San Francisco, 513 Parnassus Avenue, S-1057, San Francisco, California 94143-0451, USA.

Proteins that directly regulate tumour necrosis factor receptor (TNFR) signalling have critical roles in regulating cellular activation and survival. ABIN-1 (A20 binding and inhibitor of NF-kappaB) is a novel protein that is thought to inhibit NF-kappaB signalling. Here we show that mice deficient for ABIN-1 die during embryogenesis with fetal liver apoptosis, anaemia and hypoplasia. ABIN-1 deficient cells are hypersensitive to tumour necrosis factor (TNF)-induced programmed cell death, and TNF deficiency rescues ABIN-1 deficient embryos. ABIN-1 inhibits caspase 8 recruitment to FADD (Fas-associated death domain-containing protein) in TNF-induced signalling complexes, preventing caspase 8 cleavage and programmed cell death. Moreover, ABIN-1 directly binds polyubiquitin chains and this ubiquitin sensing activity is required for ABIN-1's anti-apoptotic activity. These studies provide insights into how ubiquitination and ubiquitin sensing proteins regulate cellular and organismal survival.
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http://dx.doi.org/10.1038/nature07575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642523PMC
February 2009

IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation.

J Exp Med 2008 May 5;205(5):1213-25. Epub 2008 May 5.

Colitis and Crohn's Disease Center, Gastroenterology Division, Department of Medicine, Biomedical Sciences Program, Program in Biological Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.

Natural killer (NK) cells are innate immune effectors that mediate rapid responses to viral antigens. Interleukin (IL)-15 and its high affinity IL-15 receptor, IL-15Ralpha, support NK cell homeostasis in resting animals via a novel trans presentation mechanism. To better understand how IL-15 and IL-15Ralpha support NK cell activation during immune responses, we have used sensitive assays for detecting native IL-15 and IL-15Ralpha proteins and developed an assay for detecting complexes of these proteins. We find that IL-15 and IL-15Ralpha are preassembled in complexes within the endoplasmic reticulum/Golgi of stimulated dendritic cells (DCs) before being released from cells. IL-15Ralpha is required for IL-15 production by DCs, and IL-15 that emerges onto the cell surface of matured DCs does not bind to neighboring cells expressing IL-15Ralpha. We also find that soluble IL-15-IL-15Ralpha complexes are induced during inflammation, but membrane-bound IL-15-IL-15Ralpha complexes, rather than soluble complexes, support NK cell activation in vitro and in vivo. Finally, we provide in vivo evidence that expression of IL-15Ralpha specifically on DCs is critical for trans presenting IL-15 and activating NK cells. These studies define an unprecedented cytokine-receptor biosynthetic pathway in which IL-15Ralpha serves as a chaperone for IL-15, after which membrane-bound IL-15Ralpha-IL-15 complexes activate NK cells via direct cell-cell contact.
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http://dx.doi.org/10.1084/jem.20071913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373851PMC
May 2008

The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals.

Immunity 2008 Mar;28(3):381-90

UCSF Colitis Center, Gastroenterology Division, Department of Medicine, Program in Biomedical Sciences, University of California at San Francisco, San Francisco, CA 94143-0538, USA.

Muramyl dipeptide (MDP), a product of bacterial cell-wall peptidoglycan, activates innate immune cells by stimulating nucleotide-binding oligomerization domain containing 2 (NOD2) -dependent activation of the transcription factor NFkappaB and transcription of proinflammatory genes. A20 is a ubiquitin-modifying enzyme that restricts tumor necrosis factor (TNF) receptor and Toll-like receptor (TLR) -induced signals. We now show that MDP induces ubiquitylation of receptor- interacting protein 2 (RIP2) in primary macrophages. A20-deficient cells exhibit dramatically amplified responses to MDP, including increased RIP2 ubiquitylation, prolonged NFkappaB signaling, and increased production of proinflammatory cytokines. In addition, in vivo responses to MDP are exaggerated in A20-deficient mice and in chimeric mice bearing A20-deficient hematopoietic cells. These exaggerated responses occur independently of the TLR adaptors MyD88 and TRIF as well as TNF signals. These findings indicate that A20 directly restricts NOD2 induced signals in vitro and in vivo, and provide new insights into how these signals are physiologically restricted.
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http://dx.doi.org/10.1016/j.immuni.2008.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606373PMC
March 2008

Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20.

J Exp Med 2008 Feb 11;205(2):451-64. Epub 2008 Feb 11.

Gastrointestinal Division, Department of Medicine, Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA.

Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor-associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain-containing adaptor inducing interferon (IFN) beta-dependent nuclear factor kappaB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated.
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http://dx.doi.org/10.1084/jem.20071108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271029PMC
February 2008

Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis.

Blood 2004 Jul 18;104(2):397-401. Epub 2004 Mar 18.

University of California, San Francisco, HSE-1300, 513 Parnassus Ave, San Francisco, CA 94143-0130, USA.

Procoagulant activity on tumor cells can enhance their ability to spread via the circulation to colonize distant organs. Toward defining the relative importance of the main host responses to coagulation for hematogenous metastasis, we examined lung metastases after intravenous injection of melanoma cells in Nf-E2(-/-) mice, which have virtually no circulating platelets; Par4(-/-) mice, which have platelets that fail to respond to thrombin; Par1 and Par2(-/-) mice, which have markedly attenuated endothelial responses to coagulation proteases; and Fib(-/-) mice, which lack fibrinogen. In a severe combined immunodeficiency (SCID) background, median lung tumor count in Nf-E2(-/-), Par4(-/-), and Fib(-/-) mice was 6%, 14%, and 24% of wild type, respectively; total tumor burden was only 4%, 9%, and 3% of wild type, respectively. Similar results were seen in a syngeneic C57BL6 background. By contrast, deficiencies of protease-activated receptor 1 (PAR1) or PAR2 did not provide protection. These results provide strong genetic evidence that platelets play a key role in hematogenous metastasis and contribute to this process by both thrombin-dependent and -independent mechanisms. Importantly, PAR4 heterozygosity conferred some protection against metastasis in this model. Thus even partial attenuation of platelet function may be sufficient to provide benefit.
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http://dx.doi.org/10.1182/blood-2004-02-0434DOI Listing
July 2004