Disease relevance of HMMR

• Here, we investigate the relationship between RHAMM and centrosomal abnormalities within multiple myeloma patient samples [1].
• The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells [2].
• Combined case-control study on Israeli and American Ashkenazi Jewish populations shows an association of RHAMM gene variants with higher risk of breast cancer in humans [3]. But another, larger study on European white population (from East Anglia, UK) has found no significant association of any RHAMM gene variants with risk of breast cancer [4].
• In melanoma, RHAMM mRNA expression was detected in metastases (80%) but not in primary tumors [5].
• Western blotting stained positive for RHAMM protein in 70% of AML patients. mRNA expression of RHAMM also was found in patients with CML (40%), renal cell carcinoma (73%), breast carcinoma (60%), and ovarian carcinoma (50%) [5].
• Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia [5].

High impact information on HMMR

• HMMR/RHAMM is an in vitro substrate for BRCA1-BARD1–mediated polyubiquitination and BRCA1 and HMMR genetically interact to control centrosome number in breast tumor– and mammary epithelium–derived cell lines [3]

• BRCA1/BARD1 modulate spindle assembly through a pathway which attenuates RHAMM function [6]
• Overexpression of the RHAMM gene by transfection into fibroblasts is transforming and causes spontaneous metastases in the lung [7].
• H-ras-transformed fibrosarcomas transfected with a dominant suppressor mutant of RHAMM exhibit a so-called revertant phenotype and are completely nontumorigenic and nonmetastatic [7].
• The loss of functional RHAMM ablates signaling within focal adhesions, in particular changes in focal adhesion kinase phosphorylation, and as a result these focal adhesions are unable to turn over in response to hyaluronan [7].
• Recombinant techniques were used to generate chimeric proteins containing either the B(X7)B motifs present in CD44 or link protein, with the amino-terminus of RHAMM (amino acids 1-238) that does not bind HA [8].
• Identification and characterization of epitopes of the receptor for hyaluronic acid-mediated motility (RHAMM/CD168) recognized by CD8+ T cells of HLA-A2-positive patients with acute myeloid leukemia [9].

Chemical compound and disease context of HMMR

• Binding and adhesion of melanoma cells to hyaluronic acid is mainly CD44 dependent as it was inhibited to 60%--80% by an anti-CD44 monoclonal antibody whereas anti-RHAMM/IHABP sera had no effect [10].
• The ability of RHAMM to bind ligand was determined through cetylpyridinium chloride (CPC) precipitations of brain tumor lysates in HA-binding assays [11].
• A complete RHAMM cDNA (1.43 kilobases (kb)) was expressed as a fusion protein with pGEX-2T in Escherichia coli HB101 and was shown to bind specifically to both biotin-labeled HA in a transblot assay and to HA-Sepharose [12].

Biological context of HMMR

• Like TPX2, RHAMM expression is up-regulated during mitosis [1].
• We postulate that augmentation of RHAMM expression within human cancers, including myeloma, can directly affect centrosomal structure and spindle integrity and potentially modulate apoptotic and cell cycle progression pathways [1].
• A receptor for hyaluronan-mediated motility (RHAMM) has been shown to promote cell locomotion [13].
• Here we describe the expression of two human RHAMM isoforms, which are generated by alternative splicing of the primary gene transcript, by a series of human breast carcinoma cell lines [2].
• This interaction domain is composed of two distinct subdomains, one of which is sufficient to mediate binding to the mitotic spindle while both domains are required for binding of RHAMM/IHABP proteins to interphase microtubules [14].

Anatomical context of HMMR

• Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells [15].
• CD34(+)45(lo/med)Scatterlo/med HPCs from granulocyte colony-stimulating factor (G-CSF)-mobilized blood and mobilized BM were compared with steady-state BM for their ability to bind hyaluronan (HA), their expression of the HA receptors RHAMM and CD44, and their motogenic behavior [15].
• Elevated expression of receptor for hyaluronan-mediated motility (RHAMM) within ex vivo diagnostic multiple myeloma plasma cells predicts for aggressive disease and patient survival [1].
• We confirm a previous study showing that the amino terminus of RHAMM interacts with microtubules and further demonstrate that a separate carboxy-terminal domain is required for centrosomal targeting [16].
• The apparently strong negative regulatory control over RHAMM expression by microenvironmental factors and by known thymic and T cell signaling molecules supports this view [13].

Associations of HMMR with chemical compounds

• These observations are consistent with the view that cyclosporin A inactivates a RHAMM-directed inhibitory mechanism [13].
• RHAMM proteins were capable of binding to hyaluronan, but not to heparin or chondroitin sulphate, in an vitro binding assay [2].
• PURPOSE: Interactions of hyaluronic acid (HA) with its binding protein RHAMM (receptor for HA-mediated motility) have been proposed as being important in promoting tumour progression and dissemination [17].
• High-avidity interactions via integrins appear to supercede the motogenicity of RHAMM and HA, suggesting that integrin avidity may regulate RHAMM [18].
• During short-term tissue culture, Mo upregulated their HA avidity and expression of ICAM-1, CD44s, and epitopes encoded by CD44v, all of which were further augmented by IFN-gamma or lipopolysaccharide, whereas RHAMM was not detectable [19].

Physical interactions of HMMR

• CD44 binds approximately five times more HA than RHAMM as determined by densitometric analysis of transblots, indicating that this protein is the major HA receptor on fibroblasts [20].

Regulatory relationships of HMMR

• Although antibodies against both receptor inhibited in vitro endothelial tube formation, only the anti-RHAMM antibody blocked basic fibroblast growth factor-induced neovascularization in mice [21].
• RHAMM is an oncogene that regulates signaling through ras and controls mitogen-activated protein kinase [extracellular signal-regulated protein kinase (ERK)] expression in embryonic murine fibroblasts [22].

Other interactions of HMMR

• Our results further demonstrate that both CD44 and receptor for hyaluronan-mediated motility (RHAMM) are involved in binding cell surface associated HA on Hfob cells [23].
• Culture of MN thymocytes on thymic epithelial layers, with or without IL-2, resulted in a lack of RHAMM expression [13].
• RHAMM is differentially expressed: significant mRNA expression was not found in normal tissues, except from testis, placenta, and thymus, or in PBMN- and CD34-separated cell samples of healthy volunteers [5].
• As others have shown that excess pericentriolar material strongly associates with abnormal mitoses, we modeled centrosomal abnormalities with exogenous RHAMM overexpression [1].
• The receptor for hyaluronan-mediated motility (RHAMM), an acidic coiled coil protein, has previously been characterized as a cell surface receptor for hyaluronan, and a microtubule-associated intracellular hyaluronan binding protein [16].

Analytical, diagnostic and therapeutic context of HMMR

• A polyclonal antibody, raised against a bacterially expressed RHAMM fusion protein, detected an 85-90 kDa protein by western blot analysis [2].
• CONCLUSIONS: RHAMM is an immunogenic antigen in leukemias and solid tumors and might be a potential target structure for cellular immunotherapies and antibody therapies [5].
• METHODS: We examined a series of 89 endometrial carcinomas and 15 normal endometrial tissues by immunohistochemistry, using a RHAMM-specific polyclonal antibody [17].
• To assess whether this motif predicts HA binding in the intact RHAMM protein, we mutated all basic amino acids in domains I and II that form part of these motifs using site-directed mutagenesis and prepared fusion protein from the mutated cDNA [8].
• Moreover, confocal microscopy showed a polarized distribution of RHAMM and F-actin, but not CD44, in cells which had become motile on HA in the presence of IL-8 [24].

References