Disease relevance of RAB8A

• Two-dimensional gel electrophoresis showed that rab8p was highly enriched in immuno-isolated basolateral vesicles carrying vesicular stomatitis virus-glycoprotein (VSV-G) but was absent from vesicles transporting the hemagglutinin protein (HA) of influenza virus to the apical cell surface [1].
• The MEL gene was identified following transfection of NIH3T3 mouse fibroblasts with DNA from a human melanoma cell line [2].
• A recombinant adenovirus stock containing the neomycin-resistance gene driven by the SV40 early promoter was used to infect the K562 and MEL hematopoietic cell lines to resistance to the antibiotic G418 [3].
• Mortality within 2 months of therapy was 20% to 25% with MEL 100 and TBI regimens, but less than 1% with MEL 200, mainly because severe neutropenia (< 500/microL) was shortened to less than 1 week due to infusion of PBSC and use of growth factor therapy [4].
• The gene shows homologies with members of the HERV-K family of human endogenous retroviruses, and it was provisionally named HERV-K-MEL [5].

Psychiatry related information on RAB8A

• Since the overall consistency of significant results was more pronounced in the subjective than in the objective part of the MEL the results fit best a circular pathogenetic model of interactions between life events, their individual evaluation by the patient, and depressive symptoms [6].
• In NMU-induced mammary carcinogenesis MEL lowered the tumour volume (although statistically non-significantly) by 30% in comparison with the control group; in DMBA-induced mammary carcinogenesis it lowered the tumour volume (2.70 +/- 0.81 cm3 vs. 0.90 +/- 0.33 cm3) and lengthened (non-significantly) the latency period (by 12 days) [7].

High impact information on RAB8A

• Analysis of human hemoglobin switching in MEL x human fetal erythroid cell hybrids [8].
• We suggest that DNA sequences that regulate beta-globin gene transcription during MEL differentiation are located both 5' and 3' to the translation initiation site [9].
• We introduced into MEL cells rabbit beta-globin gene deletion mutants and two sets of hybrid genes constructed from the inducible human beta-globin gene and noninducible human gamma-globin gene or the murine H-2Kbm1 class I MHC gene [9].
• S1 nuclease analysis of gene transcripts before and after MEL differentiation showed that induction of the rabbit beta-globin gene did not require more than 58 bp of DNA 5' to the transcription initiation site [9].
• MEL 14, a monoclonal antibody directed against this adhesion molecule, blocks lymphocyte traffic to lymph nodes and extravasation of neutrophils from blood to inflammatory sites [10].

Chemical compound and disease context of RAB8A

• Rab8-dependent Recycling Promotes Endosomal Cholesterol Removal in Normal and Sphingolipidosis Cells [11].
• Our results suggest that tyrosine transport in SK-MEL 23 melanoma cells is similar to system L transport previously characterized in other cell types [12].
• We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting [13].
• Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma [13].
• Synergistic interactions between interferon beta and carboplatin on SK-MEL 28 human melanoma cell growth inhibition in vitro [14].

Biological context of RAB8A

• Here we report the identification and the complete cDNA-derived amino acid sequence of a murine rab8-interacting protein (rab8ip) that specifically interacts with rab8 in a GTP-dependent manner [15].
• We have previously shown that Rab8 controls polarised membrane transport by modulating cell morphogenesis [5] [16].
• Rab8 has a drastic effect on cell shape, but the membrane trafficking route it regulates is poorly defined [17].
• Expression of dominant-negative Rab8 mutants or depletion of Rab8 by RNA interference inhibit protrusion formation, but promote cell-cell adhesion and actin stress fiber formation, whereas expression of the constitutively active Rab8-Q67L has the opposite effect [17].
• Prenylation of Rab8 GTPase by type I and type II geranylgeranyl transferases [18].

Anatomical context of RAB8A

• Cell fractionation and immunofluorescence analyses indicate that in MDCK cells endogenous rab8ip is present both in the cytosol and as a peripheral membrane protein concentrated in the Golgi region and basolateral plasma membrane domains, sites where rab8 itself is also located [15].
• Using a cytosol dependent in vitro transport assay in permeabilized MDCK cells we studied the functional role of rab8 in biosynthetic membrane traffic [1].
• The human gene locus c-MEL was identified following transfection of genomic DNA from the human melanoma cell line NK14; it has previously been assigned to chromosome 19 (p13.2-q13.2) by analysis of somatic cell hybrids [19].
• Rab8 promotes polarized membrane transport through reorganization of actin and microtubules in fibroblasts [20].
• Rab8 is a small Ras-like GTPase that regulates polarized membrane transport to the basolateral membrane in epithelial cells and to the dendrites in neurons [20].

Associations of RAB8A with chemical compounds

• To determine whether one enzyme plays a predominant role in Rab8 prenylation in vivo, the incorporation of [3H]mevalonate into Rab8 was measured in human embryonal kidney 293 cells under conditions where the activity of GGTaseI, but not GGTaseII, was blocked by the peptidomimetic inhibitor GGTI-298 [18].
• The modification of Rab8 by GGTaseI did not require REP, indicating that a REP-induced conformational change is not essential for exposure of the Rab carboxyl-terminal cysteine prenylation site [18].
• The activation of platelets by thrombin, a potent inducer of secretion, resulted in the phosphorylation of rab3B, rab6, and rab8 proteins, whereas no phosphorylation was observed in the presence of prostaglandin E1, which stimulates cAMP-dependent protein kinase and inhibits the secretion process [21].
• We show here that overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts [11].
• Our data suggest that in photoreceptors phosphatidylinositol-4,5-bisphosphate, moesin, actin, and rac1 act in concert with rab8 to regulate tethering and fusion of RTCs [22].

Physical interactions of RAB8A

• The activated form of Rab8 interacted with the amino-terminal region of FIP-2, whereas dominant-negative Rab8 did not [16].

Regulatory relationships of RAB8A

• We identified a coil-coiled protein (Rabin8), homologous to the rat Rabin3 that stimulated nucleotide exchange on Rab8 but not on Rab3A and Rab5 [23].
• MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway [24].

Other interactions of RAB8A

• FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis [16].
• Furthermore, we show that rat Rabin3 has exchange activity on Rab8 but not on Rab3A, supporting the view that rat Rabin3 is the rat equivalent of human Rabin8 [23].
• This report demonstrates that Rab8 and Rab13 proteins are isoprenylated in vivo and geranylgeranylated in vitro [25].
• One protein, rab16, is closely related to members of the rab3 subfamily, whereas two others are assigned as the rat homologs of canine rab8 and rab10 [26].
• The rab8 GTPase, important for basolateral vesicle targeting, was redistributed from the perinuclear Golgi region to disperse vesicles in ADPKD cells [27].

Analytical, diagnostic and therapeutic context of RAB8A

• Upon high-performance liquid chromatography (HPLC) gel filtration, melanoma cell-derived IL-1 (MEL-IL-1) exhibited molecular weight heterogeneity, and HPLC chromatofocusing revealed major activity at pH 5.0 and minor activity at pH 7 [28].
• Low beta 2-microglobulin (beta 2M) levels < or = 2.5 mg/L and MEL 200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS) [4].
• The MEL sFv-rGel fusion toxin bound to antigen-positive but not antigen-negative cells as assessed by ELISA [29].
• These results suggest that HERV-K-MEL is a source of antigens that are targeted by CTLs in melanoma patients and could therefore be used for vaccination [5].
• Nondenaturing gel filtration of MEL extract demonstrated that ErEN is a component of an approximately 160 kDa complex implying that additional proteins may regulate ErEN activity and provide increased cleavage specificity [30].

References