Disease relevance of ANXA1

• Importantly, overexpression of ANXA1 in clone 15S inhibited the extent of cell migration into rheumatoid synovial grafts transplanted into SCID mice [1].
• Since this protein modulates the anti-inflammatory actions of the steroid hormones, the purpose of this study was to investigate the effects of the female sex steroid hormone, 17beta-estradiol (E2beta), on the synthesis and secretion of ANXA1 in the human CCRF-CEM acute lymphoblastic leukemia cell line [2].
• RESULTS: ANXA1 mRNA and protein were detected in all but three adenomas studied; the protein was localized mainly, but not exclusively, to nonendocrine cells [3].
• ANXA1 and ANXA5 were also expressed in abundance in the astrocytoma [3].
• As a prelude to examining the potential role of ANXA1 in the pathophysiology of pituitary tumours, this study examined the expression, phosphorylation status and distribution of ANXA1 and the closely related protein, annexin 5 (ANXA5), in a series of pituitary adenomas and in two carcinomas [3].

High impact information on ANXA1

• Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci [4].
• The p35 protein from baculoviruses effectively prevents apoptosis by its broad-spectrum caspase inhibition [5].
• The repositioning of the amino terminus of p35 into the active site of the caspase eliminates solvent accessibility of the catalytic dyad [5].
• This may be crucial for preventing hydrolysis of the thioester intermediate, which is supported by the abrogation of inhibitory activity through mutations at the N terminus of p35 [5].
• Here we report the crystal structure of p35 in complex with human caspase-8 at 3.0 A resolution, and biochemical and mutagenesis studies based on the structural information [5].

Chemical compound and disease context of ANXA1

• The product of the baculovirus p35 gene is a specific inhibitor of a class of cysteine proteases termed caspases, and naturally functions in infected insects [6].
• Recent studies using the cytochrome P-450 prodrug cyclophosphamide exemplify how the antiapoptotic, caspase-inhibitory baculovirus protein p35 can be combined with P-450 gene-directed enzyme prodrug therapy to prolong localized, intratumoral production of cytotoxic drug metabolites without inducing tumor cell drug resistance [7].
• L4-MAb abolished the phospholipase A2 inhibitory activity of lipocortin I, but did not affect its binding to E. coli membranes or to phosphatidylserine [8].
• Using SDS polyacrylamide gel electrophoresis (SDS-PAGE), several coworkers isolated a unique membrane protein that they named p35 from hairy cells of white patients with hairy cell leukemia [9].
• Based on evidence that corticosteroids exert their anti-inflammatory action via de novo synthesis of phospholipase A2 inhibitory proteins called lipocortins, we examined effects of high dose dexamethasone and recombinant human lipocortin-1 (annexin-I) on cold-injury brain edema in the rat [10].

Biological context of ANXA1

• The effect of the glucocorticoid inducible protein annexin 1 (ANXA1) on the process of monocytic cell migration was studied using transfected U937 cells expressing variable protein levels [1].
• An antisense (AS) (36.4AS; approximately 50% less ANXA1) and a sense (S) clone (15S; overexpressing the bioactive 24-kDa fragment) together with the empty plasmid CMV clone were obtained and compared with wild-type U937 cells in various models of cell migration in vitro and in vivo [1].
• These findings provide new evidence that ANXA1 modulates gene expression [11].
• CONCLUSION: In prototype Th1 and Th2-type human T cell responses, ANXA1-derived peptides can inhibit antigen-driven cellular proliferation and cytokine production [12].
• Three genes showed strong downregulation after treatment with ANXA1 [11].

Anatomical context of ANXA1

• These data strongly support the notion that ANXA1 critically interferes with a leukocyte endothelial step essential for U937 cell, and possibly monocyte, transmigration both in vitro and in vivo [1].
• By using rapid subtraction hybridization we studied the effects of human recombinant ANXA1 and the N-terminal ANXA1 peptide on gene expression in a human larynx cell line [11].
• It is now emerging that ANXA1 is endowed with other roles, since the protein is abundant in inflammatory exudates as it is produced and released by the extravasated neutrophil [13].
• Annexin 1 (ANXA1) is the first characterized member of the annexin family of proteins able to bind (i.e. to annex) to cellular membranes in a calcium-dependent manner [14].
• Additionally, we used brefeldin A to investigate the involvement of the classical endoplasmic reticulum (ER)-Golgi pathway of protein secretion in the release of ANXA1 [15].

Associations of ANXA1 with chemical compounds

• Endogenous production by PBMC of cell surface-associated and intracellular ANXA1 in response to PHA, Der p and PPD in the presence and absence of dexamethasone was measured by specific ELISA [12].
• Two ANXA1-derived peptides, Ac2-26 and AF-2 (5-500 microM), were assessed for possible inhibition of PHA-and antigen-induced T cell proliferation (measured by 3H-thymidine uptake), while Ac2-26 was assessed for inhibition of Der p-induced interleukin (IL)-5 release and PPD-induced interferon-gamma (IFN-gamma) release (measured by ELISA) [12].
• Originally described as a phospholipase A2 (PLA2)-inhibitory protein, ANXA1 can affect many components of the inflammatory reaction besides the metabolism of arachidonic acid [14].
• The GC receptor antagonist, RU486, neither reverted the Dex-dependent ANXA1 secretion nor inhibited the increase of the [Ca2+]i induced by Dex [15].
• Furthermore, the Ca2+ ionophore, ionomycin, alone induced ANXA1 cleavage, but not its secretion [15].

Physical interactions of ANXA1

• Furthermore, we present evidence for altered neutrophil functions in rheumatoid arthritis that correspond to a significantly reduced capacity of these cells to bind annexin-I [16].
• Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies [17].

Regulatory relationships of ANXA1

• Moreover the reduction in CCR10 expression induced by ANXA1 gene deletion was rescued by intravenous treatment with low doses of ANXA1 [11].
• EGF-stimulated phosphorylation of calpactin II was much less pronounced in vesicles prepared from A-431 cells in the absence of Ca2+, although comparable amounts of the protein were detectable by immunoblotting [18].

Other interactions of ANXA1

• In vitro and in vivo studies on CCR10 regulation by Annexin A1 [11].
• AnxA2 down-regulation is not due to proteasome activation and seems to be related to the butyrate-induced cell proliferation arrest; AnxA1 and AnxA5 expression is growth-state independent [19].
• The inhibition of iNOS expression may be caused by the stimulation of IL-10 release induced by ANXA1 in macrophages [14].
• ICI 182,780, a selective inhibitor of the intracellular estrogen receptor, had no effect on the E2beta-stimulated expression and externalisation of ANXA1 [2].
• ANXA1 and its peptide act via the FPR family of receptors [20].

Analytical, diagnostic and therapeutic context of ANXA1

• METHODS: Complementary reverse transcription-polymerase chain reaction and Western blot assays were performed to study the effect of E2beta on the expression of mRNA and protein ANXA1, respectively [2].
• MEASUREMENTS: The tissue was processed for analysis of ANXA1 mRNA and protein expression by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis and immunogold electron-microscopic histochemistry [3].
• ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions [21].
• Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining [21].
• To address this hypothesis, we examined ANXA1-dependent glucocorticoid actions in co-cultures of murine corticotroph (AtT20 clone D1) and folliculo-stellate (TtT/GF) cell lines [22].

References