Annexin 1: An Endogenous Anti-Inflammatory Protein

The William Harvey Research Institute, London EC1M 6BQ, United Kingdom.
News in physiological sciences 05/2003; 18(2):60-4. DOI: 10.1152/nips.01424.2002
Source: PubMed

ABSTRACT A hallmark of inflammation is the mobilization of blood-borne leukocytes across microvessels to kill and remove the invading pathogen. For its damaging potential, leukocyte movement is finely regulated, and endogenous pathways exist to ensure the time dependency of this process. Annexin 1 and its receptor(s) are one example of these pathways.

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    • "Interestingly, cytoskeletal disruptive drugs have anti-inflammatory (Cronstein et al., 1995) and anti-proliferative roles (Dustin, 1963; Miquel et al., 1996; Tiozzo et al., 1996). Similarly ANXA1 also functions as an anti-inflammatory, anti-proliferative and apoptotic molecule (Flower and Rothwell, 1994; Perretti and Gavins, 2003), through post-translational modifications (Solito et al., 2006). "
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    ABSTRACT: Cytokeratins (CKs) constitute the cytoskeletal network and are regulated by post-translational modifications, acting not only as a mechanical support, but also in cell signaling and regulatory processes. Signaling is mediated by CK-associated proteins, such as Annexin A1 (ANXA1), a ligand of the CK18/CK8 complex. ANXA1 has a pivotal role in cellular and immunological responses, and together with CK18 have been implicated in several processes related to malignant transformation in breast cancer (BC). Our aim was to demonstrate how their interaction might be linked to BC development. We investigated transcript levels, protein expression and distribution for both targets in breast tissues of 92 patients (42 BCs and 50 benign diseases) using qPCR and immunohistochemistry, respectively. ANXA1 and CK18 mRNAs were inversely correlated, and their ratio in each TNM stage significantly differentiated BC from benign diseases (OR = 5.62). These differences did not mirror tissue protein levels, but a significant dichotomous protein distribution in tumor tissues was observed, differing from the expected co-localization observed during cell homeostasis. The disequilibrium of transcriptional levels between ANXA1/CK18 and alterations in their tissue distribution are present either in initial events or tumor progression, which suggest a critical event in BC. The broken dialog between ANXA1 and CK18 in normal breast tissues may play a critical role in BC development, and together may be used as combined targets for BC diagnostics.
    Acta Histochemica 09/2014; 116(7). DOI:10.1016/j.acthis.2014.06.008 · 1.76 Impact Factor
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    • "The annexin superfamily of calcium and phospholipid-binding proteins has been implicated in many cellular processes, including differentiation, apoptosis, proliferation and inflammation. In particular, Annexin- 1 (ANXA1) is anti-inflammatory, anti-proliferative and pro-apoptotic, and regulates differentiation (Flower and Rothwell, 1994; Perretti and Gavins, 2003; Parente and Solito, 2004; Lim and Pervaiz, 2007). The expression of ANXA1 has been studied in many types of cancer; however, there is no consensus on the role of this protein in tumor initiation and/or progression. "
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    ABSTRACT: The molecular mechanisms underlying constitutive nuclear factor-κB (NF-κB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-κB activity, suggesting that ANXA1 may be required for the constitutive activity of IκB kinase (IKK) and NF-κB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-κB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKγ or NEMO, but not IKKα or IKKβ. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-κB. Downstream targets of NF-κB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-κB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-κB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1-deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-κB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.
    Oncogene 03/2011; 30(28):3174-85. DOI:10.1038/onc.2011.28 · 8.56 Impact Factor
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    • "To ensure precise regulation, a complex network of soluble and surfacebound mediators controls leukocyte rolling on and adhesion to the endothelium as well as the subsequent transendothelial passage into the extravascular tissues [1]. Annexin 1, a member of the annexin family of Ca 2+ /lipid-binding proteins [2], has received considerable attention over the past two decades as an anti-inflammatory mediator, since it was shown to exert antiinflammatory activities in several models of inflammation, e.g. by inhibiting neutrophil extravasation [3]. The physiologic importance of its extracellular activity has been strengthened by the recent identification of annexin 1 as a specific ligand for the formyl peptide receptor family of chemoattractant receptors [4– 6]. "
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    ABSTRACT: Annexin 1 has been shown to participate through its unique N-terminal domain in the recruitment and activation of leukocytes at sites of inflammation. Peptides derived from this domain are true mimetics of the annexin 1 action in all inflammation models tested and most likely serve as the active entities generated at sites of inflammation. To elucidate mechanisms underlying peptide generation we used isolated blood leukocytes and endothelial cell monolayers. We show that following endothelial adhesion, annexin 1 was externalized from leukocytes and rapidly cleaved. Addition of purified annexin 1 to degranulating leukocytes resulted in the truncation of annexin 1, which seemed to depend on the proteolytic activity of human leukocyte elastase (HLE). The capacity of elastase to proteolytically cleave annexin 1 was confirmed using both purified annexin 1 and HLE. The identification of annexin 1 as a substrate for HLE supports the model in which annexin 1 participates in regulating leukocyte emigration into inflamed tissue through N-terminal peptides generated at inflammatory sites.
    Biochimica et Biophysica Acta 12/2006; 1763(11):1320-4. DOI:10.1016/j.bbamcr.2006.08.041 · 4.66 Impact Factor
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