Disease relevance of CSF2RA

• Previous work using DTctGMCSF produced in Escherichia coli has shown that this chimeric toxin is selectively cytotoxic to GMCSF receptor (R)-positive acute myeloid leukemia (AML) cells both in vitro and in vivo [1].
• Production of recombinant DTctGMCSF fusion toxin in a baculovirus expression vector system for biotherapy of GMCSF-receptor positive hematologic malignancies [1].
• Two gaps of less than 50 kb within the genomic locus of CSF2RA and around XE7 remain, which could not be covered with YACs, cosmids, or phages [2].
• We studied the function of GMR in human melanoma cell lines [3].
• All of the myeloid leukemias and only rare lymphoid leukemias surveyed tested positive for GMR alpha [4].

Psychiatry related information on CSF2RA

• Also, schizophrenics showed negative correlations of task performance with anterior cingulate activity suggesting that overactivity of that region, which is involved in mental effort and whose GMR was low in our larger study of schizophrenia, impairs task performance in schizophrenics [5].

High impact information on CSF2RA

• This gene, ANT3, is located approximately 1,300 kilobases from the telomere, proximal to the pseudoautosomal gene CSF2RA, and escapes X-inactivation [6].
• The gene encoding the granulocyte macrophage colony stimulating factor receptor alpha subunit (CSF2RA) has previously been mapped to the pseudoautosomal region of the human sex chromosomes [7].
• A high affinity IL-3-binding site (Kd = 140 +/- 30 pM) was reconstituted by coexpressing the DUK-1 protein and hGMR beta, indicating that hIL-3R and hGMR share the beta subunit [8].
• Sequence alignment and modeling of interleukin (IL)-3R and IL-5R identified an arginine residue at the tip of a beta turn in a highly divergent context at the F'-G' loop, close to a conserved structural element, the WSXWS motif, suggesting the possibility of a ligand association mechanism similar to the one described herein for GMR [9].
• These results indicate that the beta homodimer, which alone is insufficient for signaling, forms the functional hGMR with the alpha subunit in response to hGM-CSF [10].

Chemical compound and disease context of CSF2RA

• These results suggest a metabolic role for the low-affinity GMR in melanoma cell lines and indicate that the alpha subunit of the GMR can signal for increased glucose uptake in nonhematopoietic tumor cells [3].
• The modulation of GM-CSF-r alpha-chain upon progesterone treatment suggests a role for GM-CSF and its receptor in the pathogenesis and development of endometrial cancer [11].

Biological context of CSF2RA

• The CSF2RA and IL3RA genes are so close that their order could not be determined by two-color interphase in situ hybridization [12].
• Using long-range restriction mapping we have found that IL3RA maps to the same 190-kb restriction fragment as CSF2RA, suggesting that a cytokine receptor gene cluster may reside in the PAR [13].
• Using fluorescence in situ hybridisation (FISH), we have shown deletion of the CSF2RA and IL3RA loci on the derivative X chromosomes of all three patients [14].
• The CSF2RA gene spans at least 45 kb, and a representation of most of the gene on three overlapping cosmid clones has been obtained [15].
• We also evaluated the role of the cytoplasmic domain of the GMR alpha subunit and the results suggest that it is involved in the hGM-CSF-mediated signal transduction, but is not essential.(ABSTRACT TRUNCATED AT 250 WORDS)[16]

Anatomical context of CSF2RA

• In this paper we show that expression of the human GM-R in a heterologous cell system (primary avian erythroid and myeloid cells) confirms respective results in murine or human cell lines, but also provides new insights how the GM-R regulates progenitor proliferation and differentiation [17].
• The GMR alpha subunit was expressed only on mature granulocytes and monocytes, and IL-3R alpha was expressed on monocytes but not on mature granulocytes, and none of these subunits were expressed on lymphocytes [18].
• Our study showed expression levels for each receptor subunit--including GMR, IL-3R, and c-kit on human bone marrow and peripheral blood cells and leukemic cell lines--and revealed differential regulation of the expression of the receptor subunits [18].
• The granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor (GMR) transduces a signal that results in the proliferation, differentiation, and functional activation of hematopoietic cells [19].
• Human myeloid cell lines and primary explant human lymphocytes expressing high affinity GM-CSF receptors responded to alpha GMR antibody with increased glucose uptake [20].

Associations of CSF2RA with chemical compounds

• Only one tyrosine residue (Tyr577) existed within the region 544 to 589, and substitution of Tyr577 to phenylalanine in GMR beta 589 resulted in loss of c-fos activation [21].
• Experiments with a construct eliminating most of the intracellular portion of alpha GMR showed a 50% reduction in GM-CSF-stimulated glucose uptake with residual activity blocked by wortmannin [20].
• Searching for a proximally generated diffusible factor capable of activating PI 3-kinase, we identified hydrogen peroxide (H(2)O(2)), generated by ligand or antibody binding to alpha GMR, as the initiating factor [20].
• Proliferation assays showed that the membrane-proximal conserved region of GM-R alpha and the serine-acidic domain of beta c are required for both cell proliferation and ligand-dependent phosphorylation of a 93-kD cytoplasmic protein [22].
• As expected, solubilized membranes obtained from those cells expressing the highest number of GM-R (neutrophils and dimethyl sulfoxide-induced HL-60 cells; approximately 500-800 sites/cell) possessed the highest concentration of soluble GM-R (approximately 2-3 x 10(8) GM-R/micrograms) [23].

Physical interactions of CSF2RA

• GMR alpha in isolation binds to GM-CSF with low affinity and can signal for increased glucose uptake [24].
• Laminin and fibronectin binding to LR was found to prevent the binding of betaGMR to LR and relieved the LR inhibition of GMR [25].

Regulatory relationships of CSF2RA

• GMCSF activates NF-kappaB via direct interaction of the GMCSF receptor with IkappaB kinase beta [26].
• DTctGMCSF was selectively cytotoxic (IC50 1-10ng/ml) to GMCSF-receptor positive AML cells expressing the Pgp- or MRP-associated multi-drug resistant phenotypes, despite high level resistance to conventional chemotherapeutic agents [27].

Other interactions of CSF2RA

• Phosphorylation of tyrosine residues in the hGMR beta subunit and several cellular proteins is observed after hGM-CSF stimulation [21].
• Furthermore, the hGM-R alpha chain specifically interfered with EpoR signaling, an activity neither seen for the betac subunit of the receptor complex alone, nor for the alpha chain of the closely related Interleukin-3 receptor [17].
• Much less is known, however, about GM-R function in primary hematopoietic cells [17].
• Activation of GM-CSF receptor (GMR) triggers two distinct cytoplasmic signalling pathways, JAK2 and Ras, and is sufficient to maintain proliferation of growth factor-dependent cell lines [28].
• Since DTctGMCSF enters and kills its target cells by unique mechanisms (GMCSF-receptor binding and protein synthesis inhibition) and is not similar in structure to Pgp or MRP substrates, we postulated that it would be an active agent against therapy-resistant AML [27].

Analytical, diagnostic and therapeutic context of CSF2RA

• By pulsed-field gel electrophoresis, the precise localization of this gene, CSF2RA, within the pseudoautosomal region has been determined [15].
• The present study was designed to define the assembly of the GMR complex at the molecular level through site-directed mutagenesis guided by homology modeling with the growth hormone receptor complex [9].
• Low-affinity GMR cDNAs encoding both the membrane-bound and soluble receptors were obtained by PCR using primers corresponding to the published sequence [29].
• Cell surface expression of GMR alpha was examined using anti-GMR alpha and flow cytometry [4].
• Northern and reverse transcriptase-polymerase chain reaction analysis of GM-CSF-R alpha and -beta c (KH97) transcripts did not provide indications for the involvement of GM-CSF-R splice variants in the formation of the intermediate affinity GM-CSFR complex [30].

References