Disease relevance of SIPA1

• Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer [1].
• The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) within the human SIPA1 gene are associated with metastasis and other disease characteristics in breast cancer [1].
• SPA-1-deficient mice developed a spectrum of myeloid disorders that resembled human chronic myelogenous leukemia (CML) in chronic phase, CML in blast crisis, and myelodysplastic syndrome as well as anemia [2].
• Rap1 and SPA-1 in hematologic malignancy [3].
• Mice that are deficient for the SPA-1 gene develop age-dependent progression of T-cell immunodeficiency followed by a spectrum of late onset myeloproliferative disorders, mimicking human chronic myeloid leukemia [3].

Psychiatry related information on SIPA1

• Since both surveys use different questioning methods (SHS: telephone interview/self-administered questionnaire; SIPA Trend Surveys: personal interviews) a comparative study was carried out to test possible effects of the methods used on responses about alcohol consumption [4].

High impact information on SIPA1

• This shear-induced platelet aggregation (SIPA) is mediated by von Willebrand factor binding to platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa [5].
• CONCLUSIONS: This study demonstrates that c7E3 Fab is a potent inhibitor of SIPA, which may be an important mechanism of its beneficial effect in the treatment of arterial occlusive diseases and in the prevention of thrombotic complications of coronary artery disease after angioplasty [5].
• All agonists tested enhanced SIPA under low shear force, whereas only epinephrine augmented SIPA under high shear force [6].
• Shear-induced platelet aggregation (SIPA) is an important mechanism in thrombogenesis. von Willebrand factor (vWF) binding to platelet glycoprotein Ib (GP Ib) has been found to be crucial for platelet aggregation under the high shear force probably generated in stenosed coronary artery [6].
• These effects were, however, reversed by coexpression of the two proteins, indicating that a proper balance between Brd4 and SPA-1 in G2 is required for cell division [7].

Chemical compound and disease context of SIPA1

• This study demonstrates that cilostazol is an effective inhibitor of SIPA, which may be important for the prevention and the treatment of arterial occlusive diseases [8].

Biological context of SIPA1

• Fluorescence in situ hybridization (FISH) analysis using the human genomic clones indicated that SIPA1 was indeed mapped to chromosome 11q13, most likely to the 11q13.3 subregion [9].
• Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression [7].
• When SPA-1 was conditionally induced after the established cell adhesion, the cells gradually rounded up and detached from the dish [10].
• SIPA-1 consists of 16 exons with highly conserved exon-intron boundaries [11].
• Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR [1].

Anatomical context of SIPA1

• SPA-1 transiently expressed in HeLa cells was mostly localized at the cortical cytoskeleton and induced rounding up of the cells, whereas C3G-F conversely induced extensive cell spreading [10].
• Retroviral overexpression of SPA-1 in promyelocytic 32D cells also inhibited both activation of Rap1 and induction of cell adhesion by granulocyte colony stimulating factor without affecting differentiation [10].
• Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice [2].
• Furthermore, restoring SPA-1 gene in a SPA-1-deficient leukemic blast cell line resulted in the dissolution of Rap1GTP accumulation and concomitant loss of the leukemogenicity in vivo [2].
• In the present study, we showed that the MPDs in SPA-1(-/-) mice were associated with the increased hematopoietic stem cells expressing LFA-1 in bone marrow and their premature mobilization to spleen with extensive extramedullary hematopoiesis, resembling human chronic myelogenous leukemia (CML) [12].

Associations of SIPA1 with chemical compounds

• AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1 [13].
• The effects of low concentrations of epinephrine, ADP, and collagen on SIPA under both low shear (12 dyne/cm2) and high shear (108 dyne/cm2) force were investigated [6].
• To this end, we have addressed the influence of 2B-rVWF (Val553Met substitution) on SIPA-dependent variations of tyrosine protein phosphorylation (P-Tyr) and the effect of alphaIIbbeta3 blockers [14].
• In contrast, neither RGDS peptide nor MoAb 7E3, both known to block alphaIIbbeta3 engagement, had any effect on SIPA and pp125FAK [14].
• SIPA-induced MLC phosphorylation occurred exclusively through released nucleotides and selective antagonism of P2X(1) with MRS2159-reduced SIPA, ATP release, and potently inhibited MLC phosphorylation [15].

Physical interactions of SIPA1

• In vitro binding studies using truncated fragments and their mutants suggested that SPA-1 was bound to the PDZ domain of AF-6 via probable internal PDZ ligand motif within the GAP-related domain [13].

Co-localisations of SIPA1

• Immunostaining analysis revealed that SPA-1 and RapV12 were co-localized with AF-6 at the cell attachment sites [13].

Regulatory relationships of SIPA1

• Recent studies reveal that deregulated Rap1 activation in SPA-1-deficient mice causes enhanced expansion of the bone marrow hematopoietic progenitors, but induces progressive unresponsiveness or anergy in T cells [3].

Other interactions of SIPA1

• Human genomic clones, which hybridized with both mouse and human SIPA1 cDNA but not with RAP1GAP cDNA, were then isolated [9].
• These results suggested that products of SPA-1 and rap1GAP genes, albeit comparable GAP activity for Rap1 and Rap2, functioned in the distinct contexts depending on cell types and/or states [16].
• During the course of cloning SIPA-1, the MEN1 gene was identified, thus excluding human SIPA-1 as a candidate for this disease [11].
• SPA-1 cDNA encodes a 130-kDa protein (p130(SPA-1)) consisting of proline-rich regions and rap1GAP-related domain followed by a coiled-coil stretch [16].
• The predicted SIPA-1 protein is highly homologous to the mouse protein, particularly in the region of the GAP-related domain at the amino terminus and the leucine zipper at the carboxy terminus [11].

Analytical, diagnostic and therapeutic context of SIPA1

• This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA [5].
• SIPA was quantitated by flow cytometry as the disappearance of single platelets (DSP) in the sheared sample in the presence of vWF, relative to a control in the absence of shear and vWF [17].
• OBJECTIVES: The goal of this study was to identify differences in shear-induced platelet aggregation (SIPA) between patients who did or did not experience subacute stent thrombosis (SAT) [18].
• The antibody inhibited completely ristocetin-induced platelet aggregation (RIPA) and high shear stress-induced platelet aggregation (SIPA) [19].
• RESULTS: There were significant increases in not only adenosine phosphate (ADP)- and collagen-induced platelet aggregation but also in SIPA during exercise by the patient control group [20].

References