Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Abstract

The TCL1 oncogene at 14q32.1 is involved in the development of human mature T-cell leukemia. The mechanism of action of Tcl1 is unknown. Because the virus containing the v-akt oncogene causes T-cell lymphoma in mice and Akt is a key player in transduction of antiapoptotic and proliferative signals in T-cells, we investigated whether Akt and Tcl1 function in the same pathway. Coimmunoprecipitation experiments showed that endogenous Akt1 and Tcl1 physically interact in the T-cell leukemia cell line SupT11; both proteins also interact when cotransfected into 293 cells. Using several AKT1 constructs in cotransfection experiments, we determined that this interaction occurs through the pleckstrin homology domain of the Akt1 protein. We further demonstrated that, in 293 cells transfected with TCL1, the endogenous Akt1 bound to Tcl1 is 5-10 times more active compared with Akt1 not bound to Tcl1. The intracellular localization of Tcl1 and Akt1 in mouse fibroblasts was investigated by immunofluorescence. When transfected alone, Akt1 was found only in cytoplasm whereas Tcl1 was localized in the cytoplasm and in the nucleus. Interestingly, Akt1 was also found in the nucleus when AKT1 was cotransfected with TCL1, suggesting that Tcl1 promotes the transport of Akt1 to the nucleus. These findings were supported by the intracellular localization of Akt1 or Tcl1 when Tcl1 or Akt1, respectively, were confined to the specific cellular compartments. Thus, we demonstrate that Tcl1 is a cofactor of Akt1 that enhances Akt1 kinase activity and promotes its nuclear transport.

Dissecting Oct3/4-Regulated Gene Networks in Embryonic Stem Cells by Expression Profiling

“…This was originally demonstrated in T-cells [42], [59]–[61], but we find that the level of p-Ser.473-Akt1 is proportional to the level of Tcl1, and thus, the same mechanism also seems to function in ES cells. The rescue of the siTcl1-induced phenotype by a constitutively active form of Akt1 implies that Tcl1 acts through Akt1 in ES cells.…”

“…It has been shown that Tcl1 enhances the kinase activity of Akt1 [42]. This was originally demonstrated in T-cells [42], [59]–[61], but we find that the level of p-Ser.473-Akt1 is proportional to the level of Tcl1, and thus, the same mechanism also seems to function in ES cells.…”

“…The only known function of Tcl1 protein is to enhance the kinase activity of Akt1 (thymoma viral proto-oncogene 1) in leukemia cells [42]. Akt1 is a key kinase in the Ras/PI3K/Akt1 signaling pathway [43].…”

CD5+CD23+ leukemic cell populations in TCL1 transgenic mice show significantly increased proliferation and Akt phosphorylation

“…As we previously reported that Tcl1 functions as co-activator of Akt, 19 we analyzed the status of Akt activation in CD5 + CD19 + cells from TCL1 transgenics. The level of phospho-Akt (pS473) and phospho-ERK1/2(pT202/pY204) were measured before and after PMA stimulation.…”

“…11-13 We previously reported that Tcl1 functions as a co-activator of Akt and Tcl1 expression in B-CLL is regulated by miR-29 and miR-181 . 12,19 To determine whether treatments with microRNAs targeting TCL1 could inhibit B-CLL in mice, we generated TCL1 transgenic mice bearing 3′ and 5′ UTRs of human TCL1 .…”