Disease relevance of NLRP2

• Two human pancreatic cell lines, PAN1 and BXPC3, expressed gastrin at both the RNA and protein levels and are shown to be representative of human pancreatic adenocarcinomas in terms of gastrin expression [1].
• We hypothesized that polymorphisms of NBS1 are associated with breast cancer risk [2].
• Nijmegen breakage syndrome 1 (NBS1) protein is one of the key proteins that participates in recognition and repair of DSBs in humans [2].
• Increased risk of gastrointestinal lymphoma in carriers of the 657del5 NBS1 gene mutation [3].
• Although PAN 1 is expressed by gonococci during gonorrhea, the function of the PAN proteins remains unknown [4].

High impact information on NLRP2

• We showed that Akl1 promotes phosphorylation of Pan1 in this complex and reduces the endocytic ability of the cell, as does Prk1 [5].
• Gastrin antiserum synergized with both taxotere and gemcitabine in inhibiting the in vitro growth of the PAN1 cell line with the inhibitory effect of the antiserum increasing from 12.7% to 70.2% with taxotere (P < 0.05) and 28.6% with gemcitabine (P < 0.01) after controlling for the effects of the cytotoxics [1].
• Gastrin antisense-transfected PAN1 cells had increased sensitivity to the antiproliferative effects of both gemcitabine (IC50 of > 100 microg/ml reduced to 0.1 microg/ml) and taxotere (IC50 of 20 microg/ml reduced to < 0.01 microg/ml) when compared with vector controls [1].
• Both PYPAF2 and PYPAF3 mRNAs are broadly expressed in a variety of tissues; however, neither is expressed in skeletal muscle, and only PYPAF2 mRNA is expressed in heart and brain [6].
• In gene transfer experiments PAN1 enhances caspase-1 activation and IL-1beta secretion in collaboration with ASC [7].

Biological context of NLRP2

• In gene transfection studies PAN1 manifests an inhibitory influence on NF-kappaB activation induced by various pro-inflammatory stimuli, including tumor necrosis factor TNFalpha and interleukin-1beta (IL-1beta) [7].
• Interestingly, the hPAN nuclease complex has a higher substrate specificity to poly(A) RNA upon its association with PABP [8].
• Polymorphisms and haplotypes of the NBS1 gene are associated with risk of sporadic breast cancer in non-Hispanic white women <=55 years [2].
• These findings imply that heterozygous NBS1 germline mutations may contribute significantly to the overall incidence of NHL, especially of the gastrointestinal tract, in Central Europe. (c) 2006 Wiley-Liss, Inc [3].
• The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families, characterised by different mutations in the NBS1 gene [9].

Anatomical context of NLRP2

• We propose that PAN1 functions as a modulator of the activation of NF-kappaB and pro-caspase-1 in macrophages [7].
• Conversely, reducing endogenous levels of PAN1 using small interfering RNA significantly reduced LPS-induced secretion of IL-1beta in monocytes [7].
• Ca(2+)versus Mg(2+) Coordination at the Nucleotide-binding site of the Sarcoplasmic Reticulum Ca(2+)-ATPase [10].
• Heat-induced phosphorylation of NBS1 in human skin fibroblast cells [11].
• We compared radiation-induced NBS1 foci in peripheral blood lymphocytes (PBLs) from 46 sporadic breast cancer patients and 30 healthy cancer-free volunteers [12].

Associations of NLRP2 with chemical compounds

• In contrast to the insulin gene, however, neither the synergistic effect of the Pan1 expression on the IPF1-induced promoter activation nor the glucose responsiveness of the activity was observed for the GK gene promoter [13].
• 2. Three peptides isolated from nematodes, AF-1, AF-2 and PAN-1 had mainly inhibitory effects with thresholds of around 1 nM [14].

Physical interactions of NLRP2

• We also show here that PAN1 binds via its PYRIN domain to ASC, an adapter protein involved in caspase-1 activation [7].

Regulatory relationships of NLRP2

• Conversely, reducing endogenous levels of PAN1 using small interfering RNA enhanced LPS-induced production of ICAM-1 (intercellular adhesion molecule 1), an NF-kappaB-dependent gene [7].

Other interactions of NLRP2

• PAN1 protein expression is regulated by lipopolysaccharide (LPS) and interferons (IFNbeta and IFNgamma) in THP-1 macrophage cells [7].

Analytical, diagnostic and therapeutic context of NLRP2

• The results of immunofluorescent staining and Western blot analysis showed that NBS1 proteins are phosphorylated after exposure to heat in the nucleus of a normal skin fibroblast cell line (82-6 cells) [11].
• Although FISH technique detected translocation t(14q;21q) in 4 metaphases, deletion 657del5 in exon 6 of the NBS1 gene associated with NBS in Slavic population was not confirmed [15].

References