Disease relevance of RPSA

• Coimmunoprecipitation analysis showed that, upon incubation with CNF1+ E. coli K1 but not with Deltacnf1 mutant, focal adhesion kinase and paxillin were recruited and associated with 67LR [1].
• An in vitro drug sensitivity assay indicated that down-regulation of 37LRP by an antisense technique could significantly enhance the cytotoxicity of anticancer drugs to gastric cancer cells [2].
• In this study, we demonstrated that human multiple myeloma cell lines (HMCL) and murine 5T2MM cells express 67LR [3].
• The correlations between overexpression of the 67LR and lymph node metastasis were statistically significant (p < 0.07) [4].
• In mammary carcinomas, however, the biologic role of 67LR has been less clear [5].

High impact information on RPSA

• Indeed, mutant LAMR1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis [6].
• Furthermore, because selectivity was not observed in vitro or in transient transactivation experiments, these findings suggest that an understanding of the selectivity mechanism may require an analysis of the endogenous p40 locus [7].
• p37 and p40 are two cloned gene products of the five-subunit human cellular DNA replication factor activator 1 (A1) protein complex (also called replication factor C) [8].
• The 67-kDa laminin receptor (67LR) is a nonintegrin cell-surface receptor with high affinity for laminin, which plays a key role in tumor invasion and metastasis [9].
• In vitro G-CSF treatment, alone or combined with exposure to marrow-derived endothelial cells, induced 67LR up-regulation in marrow HSCs; moreover, anti-67LR antibodies significantly inhibited transendothelial migration of G-CSF-stimulated marrow HSCs [9].

Chemical compound and disease context of RPSA

• As angiogenesis in the pathological setting of proliferative retinopathy is a major cause of blindness in the Western world we examined the expression of 67LR in a murine model of hyperoxia-induced retinopathy that exhibits retinal neovascularization [10].
• Adeno-associated virus (AAV) vectors readily express the gene for geneticin-resistance under control of the AAV p40 promoter when chromosomally integrated at low copy number in mammalian cells [11].
• In the present work we investigate the effects of progestins and estrogen on the expression of 67LR in two sublines of the T47D human breast cancer cells: weakly tumorigenic, poorly invasive parental T47D cells and a highly tumorigenic, more invasive T47Dco subclone [12].

Biological context of RPSA

• Fluorescent in situ hybridization localized the 37LRP/p40 active gene on chromosome 3 in the locus 3p21.3 which, interestingly, is a hot spot for genetic alterations in several cancers and particularly in small cell lung carcinoma [13].
• Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53 [14].
• Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21.3 [13].
• 67LR has been shown to mediate the actions of LN through binding to CDPGYIGSR, a 9 amino acid sequence from the B1 chain of LN [3].
• MM cell migration was partially blocked by peptide 11, a synthetic nonapeptide derived from this amino sequence and also by a blocking antiserum against 67LR [3].

Anatomical context of RPSA

• Immunolabeling of the original tissue with antibodies against these two genes confirmed overexpression, validating our strategy: 67LR was not expressed in the normal urothelium but was present in the tumor, whereas TATI expression was confined to umbrella cells in the normal urothelium, but extended to all cell layers in the tumor [15].
• The 67 kD laminin receptor (67LR) binds laminin-1 (LN), major component of the basement membrane, with high affinity [3].
• CD38(bright+) plasma cells in fresh multiple myeloma (MM) bone marrow (BM) samples showed weaker 67LR expression, but expression increased after direct exposure to a BM endothelial cell line (4LHBMEC) [3].
• The authors explored the potential biologic significance of expression of 67LR in 148 patients with axillary lymph node negative breast carcinoma [5].
• We investigated the role of 67LR in granulocyte colony-stimulating factor (G-CSF)-induced mobilization of CD34(+) hematopoietic stem cells (HSCs) from 35 healthy donors [9].

Associations of RPSA with chemical compounds

• METHODS: Formalin fixed, paraffin embedded histologic sections were immunohistochemically evaluated for 67LR using monoclonal antibody MLuC5 [5].
• Upon incubation of the most highly purified fractions with Mn-ATP or Mg-ATP, p40 was the only protein phosphorylated on tyrosine [16].
• 32P-labeled p40 immunoprecipitated from extracts of metabolically labeled cells by affinity-purified anti-p40 antibodies contained both phosphoserine and phosphotyrosine [16].
• In the presence of a synthetic peptide (peptide G) corresponding to the 67LR laminin binding site, the rate of laminin-1 degradation by the cysteine proteinase cathepsin B was significantly increased, and a new proteolytic fragment particularly active in in vitro cell migration assays was generated [17].
• Moreover, cytokine treatment resulted in down-modulated expression of the alpha6 integrin subunit and the 67LR [18].

Other interactions of RPSA

• TATI was more consistently overexpressed than 67LR in all tumor grades and stages [15].
• We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct [14].
• Nevertheless, in the subgroup of 67LR positive patients, positivity for estrogen receptor was associated with significantly longer overall survival (P = 0.008) [5].

Analytical, diagnostic and therapeutic context of RPSA

• Immunofluorescence microscopy and ligand overlay assays showed that 67LR is present on the HBMEC membrane and interacts with CNF1 protein as well as the CDPGYIGSR laminin peptide [1].
• Sequence analysis revealed that the MGr1-Ag and 37LRP genes shared the same coding sequence [2].
• We have previously shown that 67LR detection in PC tissues from radical prostatectomy (RP) specimens is an independent predictor of biochemical (PSA) relapse in patients with clinically localized PC [19].
• This retrospective study was designed to investigate the relationship between overexpression of the 67 kD laminin receptor (67LR) using immunohistochemistry, and several clinicopathological parameters including overall survival in human gastric adenocarcinoma [4].
• Although the overexpression of the 67LR tended to correlate with lower survival rates, the correlation was not statistically significant due to the limited sample size [4].

References