Human CCL17/TARC (hCCL17) and CCL22/MDC (hCCL22) interact with their receptor CCR4, playing pivotal roles in various Th2 cell-dominant diseases. Rat Ccl17, Ccl22 and Ccr4 share 63.4%, 65.2% and 87.5% homology at the amino acid level, respectively, compared with their human homologues. Rat Ccl22 has been demonstrated to interact with rat Ccr4. However, it is not known whether rat Ccl17 is a functional ligand for rat Ccr4 and whether rat Ccr4 can interact with hCCL17 and hCCL22. In this study, we cloned rat Ccl17 and Ccr4 cDNA from rat thymus and expressed the recombinant rat Ccl17. The binding assay indicated rat Ccl17 could saturably bind rat Ccr4, and this binding could be competitively inhibited by unlabeled rat Cc17, hCCL17 or hCCL22. Both rat and human CCL17 or CCL22 could induce the chemotactic migration and calcium mobilization in rat Ccr4-transfected cells. They could also desensitize each other’s effect on chemotaxis and calcium mobilization. Furthermore, both rat Ccl17 and hCCL17 could induce significant receptor internalization in rat Ccr4-EGFP transfected cells. These results demonstrated the conserved CCL17/CCR4 interaction in rats and the further cross-species interaction of rat Ccr4 with hCCL17 and hCCL22. Likewise, they provided the molecular basis for the investigation of physiological and pharmacological roles of CCR4, its ligands, and their antagonists in rat disease models.
TIAN LinJie1,2, QI Hui1,2, XIE Yuan1,2, ZHANG YingMei1,2, ZHANG WenJuan1,2, SUN XiangYu1,2, WANG Ying1,2 & MA DaLong1,2 1 Laboratory of Medical Immunology, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China
PDCD5 is a novel apoptosis-related gene. Overexpression of PDCD5 facilitates apoptosis in various tumor cells. Here, we investigated the roles of recombinant human PDCD5 (rhPDCD5) protein in chemosensitivities of hematologic malignancies. The rhPDCD5 increased the in vitro cytotoxicity of daunorubicin (DNR), adriamycin (ADM) and As2O3 in three hematologic tumor cell lines. In vivo studies showed that DNR combined with rhPDCD5 significantly suppressed tumor growth of U937 xenograft nude mice compared with DNR alone. In conclusion, rhPDCD5 combined with the chemotherapeutic drug has greater efficacy than chemotherapy alone, and rhPDCD5 is a very promising chemosensitizer.
WANG YanFangSHI LinSONG QuanShengZHANG YingMeiLOU YaXinZHENG YiMA DaLongWANG YingKE XiaoYan
CKLF (chemokine-like factor)-like MARVEL (MAL and related proteins for vesicle trafficking and mem-brane link domain) transmembrane domain containing (CMTM) is a novel gene family. One member of this family, CMTM2, also named chemokine-like factor superfamily 2 (CKLFSF2), is expressed highly in the testis and moderately in the prostate, marrow and peripheral blood cells. However, the function of human CMTM2 remains unknown. Here, we found that CMTM2 was upregulated in 5α-dihydrotestos- terone (DHT)-treated LNCaP cells. We investigated the relationship between CMTM2 and the androgen receptor. Our results showed that CMTM2 enhanced DHT-mediated androgen receptor (AR) transacti-vation and the expression of prostate specific antigen (PSA). We also observed that CMTM2 enhanced the AR protein level, which was reversed by silencing endogenous CMTM2 expression, which sug-gested that CMTM2 might play an important role in maintaining the AR protein level. We also found that CMTM2 suppressed Akt activation. A previous study showed that Akt could phosphorylate AR at Ser210 and Ser790 and lead to AR ubiquitylation and degradation as well as suppression of AR activity. Taken together, suppressing Akt activation and increasing the AR protein level might be one of the mechanisms for the CMTM2-mediated enhancement of AR transactivation.
LIU DaZhenYIN CaiHuaZHANG YingMeiTIAN LinJieLI TingLI DanMA DaLongGUO YingLuWANG Ying
