Antiapoptotic function of charged multivesicular body protein 5: A potentially relevant gene in acute myeloid leukemia

Abstract

In recent years, RNA interference (RNAi) has been widely used to uncover gene function or pathway context of novel genes. In our study, we describe a short-hairpin RNA-based RNAi screening of a set of functionally uncharacterized human genes for their possible capability to inhibit apoptosis. We thereby identified a new antiapoptotic function for CHMP5 (charged multivesicular body protein 5), which was confirmed by overexpression and rescue assays. Furthermore, caspase assays showed that CHMP5 silencing induced caspase cascade activation mainly through extrinsic apoptosis pathway. Based on genome-wide expression array profiling, a possible regulatory role of CHMP5 on apoptosis-associated genes and different signaling pathways including nuclear factor kappa B was revealed. In addition, we found significantly higher CHMP5 mRNA levels in acute myeloid leukemia patients. This observation together with the antiapoptotic feature of CHMP5 suggests a possible oncogenic function for this gene in leukemogenesis.

Anti-CHMP5 single chain variable fragment antibody retrovirus infection induces programmed cell death of AML leukemic cells in vitro

“…Moreover, our studies are consistent with previous studies which show that CHMP5 is an anti-apoptotic gene [8,9] . Furthermore, in agreement with these previous studies, we found that the CHMP5 gene expression is significantly increased in de novo or relapsed AML, indicating that it may participate in leukemogenesis [8,9] .…”

“…Moreover, our studies are consistent with previous studies which show that CHMP5 is an anti-apoptotic gene [8,9] . Furthermore, in agreement with these previous studies, we found that the CHMP5 gene expression is significantly increased in de novo or relapsed AML, indicating that it may participate in leukemogenesis [8,9] . As shown in Figure 1, after CHMP5 is inhibited by RNA interference in the AML leukemic cell line, U937, the expression of the CHMP5 protein is significantly decreased, and the leukemic cells are induced to undergo apoptosis [8] .…”

“…Functional analyses of CHMP5 are performed using an RNAi and protein overexpression strategy in our lab. We found CHMP5 is an anti-apoptotic gene [8] , which is consistent with previous findings by Shahmoradgoli et al [9] . Moreover, our data confirmed previous findings showing that CHMP5 is significantly increased in de novo or relapsed acute myeloid leukemia, indicating that it may participate in leukemo genesis [8,9] .…”

“…We found CHMP5 is an anti-apoptotic gene [8] , which is consistent with previous findings by Shahmoradgoli et al [9] . Moreover, our data confirmed previous findings showing that CHMP5 is significantly increased in de novo or relapsed acute myeloid leukemia, indicating that it may participate in leukemo genesis [8,9] . Immunofluorescence experiments using a monoclonal antibody produced by our lab suggested that the CHMP5 protein was expressed at low levels in the cytosol of 293T cells and normal blood mononuclear cells from healthy volunteers.…”

The role of charged multivesicular body protein 5 in programmed cell death in leukemic cells

“…Functional analyses of CHMP5 have been carried out in our lab using RNAi and protein overexpression strategies. We found that CHMP5 is an anti-apoptotic gene [11], consistent with the findings of Shahmoradgoli et al [12]. Moreover, we also found that CHMP5 was significantly increased in de novo or relapsed acute leukemia, indicating that it may participate in leukemogenesis [11,12].…”