Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo

Abstract

Protooncogene T-cell leukemia 1 (TCL1), which is implicated in human T-cell prolymphocytic leukemia (T-PLL), interacts with Akt and enhances its kinase activity, functioning as an Akt kinase co-activator. Two major isoforms of TCL1 Protooncogenes (TCL1 and TCL1b) are present adjacent to each other on human chromosome 14q.32. In human T-PLL, both TCL1 and TCL1b are activated by chromosomal translocation. Moreover, TCL1b-transgenic mice have never been created. Therefore, it remains unclear whether TCL1b itself, independent of TCL1, exhibits oncogenicity. In co-immunoprecipitation assays, both ectopic and endogenous TCL1b interacted with Akt. In in vitro Akt kinase assays, TCL1b enhanced Akt kinase activity in dose- and time-dependent manners. Bioinformatics approaches utilizing multiregression analysis, cluster analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, Venn diagrams and Gene Ontology (GO) demonstrated that TCL1b showed highly homologous gene-induction signatures similar to Myr-Akt or TCL1. TCL1b exhibited oncogenicity in in vitro colony-transformation assay. Further, two independent lines of β-actin promoter-driven TCL1b-transgenic mice developed angiosarcoma on the intestinal tract. Angiosarcoma is a rare form of cancer in humans with poor prognosis. Using immunohistochemistry, 11 out of 13 human angiosarcoma samples were positively stained with both anti-TCL1b and anti-phospho-Akt antibodies. Consistently, in various cancer tissues, 69 out of 146 samples were positively stained with anti-TCL1b, out of which 46 were positively stained with anti-phospho-Akt antibodies. Moreover, TCL1b structure-based inhibitor ‘TCL1b-Akt-in' inhibited Akt kinase activity in in vitro kinase assays and PDGF (platelet-derived growth factor)-induced Akt kinase activities—in turn, ‘TCL1b-Akt-in' inhibited cellular proliferation of sarcoma. The current study disclosed TCL1b bears oncogenicity and hence serves as a novel therapeutic target for human neoplastic diseases.

Prognostic value of the PIK3CA, AKT, and PTEN mutations in oral squamous cell carcinoma: literature review

“…There are three isoforms of this kinase: AKT 1 (PKB α), AKT 2 (PKB β), and AKT 3 (PKB γ). The first two kinases can be found in most cells, while the presence of AKT3 is restricted to the brain, testis, heart, kidney, lung, and skeletal muscle [ 53 ]. It is believed that each isoform participates in different processes.…”

“…Gene amplification is one of the basic mechanisms involved in the activation of these oncogenes. Correlation between the presence of AKT gene mutations and poor prognosis was observed in cancer of the oral cavity, skin, prostate, pancreas, liver, stomach, endometrium, breast, brain, and haematological neoplasm [22,40,41,[52][53][54][55][57][58][59][60][61][62][63].…”

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

“…Here, we have predicted a functional relationship between TCL6 and its neighboring protein-coding gene, TCL1B . TCL1B is a co-activator of the protein kinase AKT1 in T-cell leukemias and it has oncogenic activity in vivo 13,14 . According to our results, TCL6 and TCL1B are highly associated with ETV6-RUNX1-positive pediatric B-ALL, in which the AKT pathway plays a major role 15 .…”

Identification of candidate genes for Parkinson's disease through blood transcriptome analysis in LRRK2-G2019S carriers, idiopathic cases, and controls

“…TCL1B, T-cell lymphoma/leukemia 1B oncogene, is involved in the development of T-cell leukemia. TCL1B is also an activator of Akt, a kinase involved in neuron survival (Hashimoto et al, 2013). Failure of Akt signaling has been reported to underlie dopamine neuron degeneration in PD (Greene et al, 2011).…”