Disease relevance of Hmmr

• Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor) [1].
• Rhamm deficiency significantly decreased the number of aggressive fibromatosis tumors formed, but did not alter the number of gastrointestinal polyps [1].
• Cell culture studies show that Rhamm regulates cell proliferation in both fibroblasts and fibromatosis cells under conditions of low density, but not high density [1].
• The RHAMM gene location and its ability to transform cells when overexpressed implicate RHAMM as a possible candidate gene in the pathogenesis of the recently described t(5;14)(q33-q34;q11) acute lymphoblastic leukemias [2].
• Moreover, tumor cells treated with soluble RHAMM are unable to form lung metastases [3].

High impact information on Hmmr

• Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression [3].
• Overexpression of RHAMM is transforming and is required for H-ras transformation [3].
• The hyaluronan (HA) receptor RHAMM is an important regulator of cell growth [3].
• The molecular mechanism underlying growth control by RHAMM and other extracellular matrix receptors remains largely unknown [3].
• We report that soluble RHAMM induces G2/M arrest by suppressing the expression of Cdc2/Cyclin B1, a protein kinase complex essential for mitosis [3].

Biological context of Hmmr

• Investigation of two interspecific backcrosses localized the mouse RHAMM (Hmmr) locus 18 cM from the centromere of mouse chromosome 11 within a region of synteny homology with human chromosome 5q23-q35 genes [2].
• To determine a link between HA-stimulated tyrosine phosphorylation and the resulting cell locomotion, cytoskeletal reorganization was examined in C3 cells plated on fibronectin and treated with HA or anti-RHAMM antibody [4].
• Using immunohistochemistry and RT-PCR, we show that Rhamm, a protein with an important role in wound healing and neoplastic progression, is also expressed at high levels in aggressive fibromatosis [1].
• We describe the isolation and characterization of the murine gene encoding RHAMM, a hyaluronan receptor which regulates focal adhesion turnover, is required for cell locomotion and is a critical downstream regulator of ras transformation [5].
• The IHABP gene consists of 18 exons and spans more than 25kb [6].

Anatomical context of Hmmr

• Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity [4].
• A full-length human RHAMM cDNA clone was isolated by a combination of screening a human breast cDNA expression library with the murine RHAMM 2 cDNA as well as 5' RACE and RT-PCR using messenger RNA from human breast cell line (MCF-10A) [7].
• RHAMM was detected in neurons of cerebral cortex and most subcortical and brainstem structures at postnatal day 1 and exhibited an adult distribution pattern by postnatal day 5 [8].
• Immunohistochemically, RHAMM was found in the vast majority of neurons and in many oligodendrocytes throughout brain, with heterogeneous levels among cell populations, and was confined to the somata and initial processes of these cells [8].
• We identify a requirement for Rhamm in the localization of CD44 to the cell surface, formation of CD44-ERK1,2 (extracellular-regulated kinase 1,2) complexes, and activation/subcellular targeting of ERK1,2 to the cell nucleus [9].

Associations of Hmmr with chemical compounds

• Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM [10].
• We also found that RHAMM had an elevated level of expression in all the HCC samples we examined and it was induced during the G2/M phase of regenerating mouse hepatocytes after partial hepatectomy [11].

Regulatory relationships of Hmmr

• Peptides corresponding to the HA-binding motif of RHAMM also suppressed TGF-beta 1-induced increases in motility rate [12].

Other interactions of Hmmr

• Rhamm-/- mice were crossed with Apc/Apc1638N mice, which harbor a targeted mutation in the Apc gene predisposing animals to gastrointestinal and aggressive fibromatosis tumors [1].
• A minor transcript containing exon 4, namely RHAMM v4, encodes a 73-kDa protein, as demonstrated by isoform-specific antibodies [5].
• Down-regulation of RHAMM by use of dominant negative mutants or antisense of mRNA also decreases Cdc2 protein levels [3].
• This provides direct evidence that the RHAMM-type HABMs in Spacrcan are involved in hyaluronan binding [13].
• TGF-beta 1 stimulation of cell locomotion utilizes the hyaluronan receptor RHAMM and hyaluronan [12].

Analytical, diagnostic and therapeutic context of Hmmr

• One of these, RHAMM variant 4 (RHAMMv4), is transforming when overexpressed and regulates Ras signaling (Hall et al.). Here we note using flow cytometry and confocal analysis that RHAMM isoforms encoding exon 4 occur both on the cell surface and in the cytoplasm [14].
• Comparison of cDNA clones and RT-PCR products with the genomic clones identified alternately spliced exons in both the coding and 5' noncoding regions of RHAMM [5].
• In this study, we explored whether RHAMM is a potential target for dendritic cell (DC) immunotherapy [15].

References