TRIB2 regulates normal and stress-induced thymocyte proliferation

Abstract

TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation of developing thymocytes is tightly controlled to prevent leukemic transformation of T cells. Here we examine Trib2 loss in murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. Trib2−/− developing thymocytes show increased proliferation, and Trib2−/− mice have significantly higher thymic cellularity at steady state. During stress hematopoiesis, Trib2−/− developing thymocytes undergo accelerated proliferation and demonstrate hypersensitivity to 5-fluorouracil (5-FU)-induced cell death. Despite the increased cell death post 5-FU-induced proliferative stress, Trib2−/− mice exhibit accelerated thymopoietic recovery post treatment due to increased cell division kinetics of developing thymocytes. The increased proliferation in Trib2−/− thymocytes was exacerbated under oncogenic stress. In an experimental murine T-cell acute lymphoblastic leukemia (T-ALL) model, Trib2−/− mice had reduced latency in vivo, which associated with impaired MAP kinase (MAPK) activation. High and low expression levels of Trib2 correlate with immature and mature subtypes of human T-ALL, respectively, and associate with MAPK. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumor suppressor function.

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

“…It is interesting to speculate that TRIBs may have a role in lineage decisions or phenotypic characteristics of myeloid and lymphoid leukemias, which may be determined by their specific cellular substrates. While it was shown that TRIB2 is a transcriptional target of the T cell transcription factor NOTCH1 [74], the absence of TRIB2 in a murine TRIB2-knockout model [75] was found to accelerate NOTCH1-driven T-ALL (Figure 5). This work also revealed a novel tumor suppressor-like function for TRIB2 in the cell cycle and proliferation of early T cell progenitor cells, and associated high levels of TRIB2 expression with early immature T-ALL and deregulated MAPK signaling [75].…”

“…While it was shown that TRIB2 is a transcriptional target of the T cell transcription factor NOTCH1 [74], the absence of TRIB2 in a murine TRIB2-knockout model [75] was found to accelerate NOTCH1-driven T-ALL (Figure 5). This work also revealed a novel tumor suppressor-like function for TRIB2 in the cell cycle and proliferation of early T cell progenitor cells, and associated high levels of TRIB2 expression with early immature T-ALL and deregulated MAPK signaling [75]. TRIB2 is cyclically expressed during the cell cycle and has the ability to promote the proteasomal degradation of the mitotic regulator CDC25C, which might explain some of the uncontrolled proliferation characteristics of leukemia [25].…”

TRIB2 knockdown as a regulator of chemotherapy resistance and proliferation via the ERK/STAT3 signaling pathway in human chronic myelogenous leukemia K562/ADM cells

“…It is known that TRIB2 is expressed in mammals. TRIB protein family members encode pseudo-kinase proteins that are highly conserved in evolution, and act as adaptors in signaling pathways for important cellular processes (6,7). Previous studies have focused on the pathological role of TRIB2 in various diseases, including CML, and metabolic and neurological diseases, in which it has been identified as a critical signaling modulator and mediator (8,9).…”

A screen for targets of the Drosophila pseudokinase Tribbles identifies Neuralized and Mindbomb, ubiquitin ligases that mediate Notch signaling

“…The connection of Trbl to Notch signaling is significant in light of the association of Tribs 2 and 3 in mammalian systems with Notch-dependent tumor formation (reviewed in Stein et al, 2015). Trib2 was identified as a downregulated gene upon g-secretase inhibitor treatment of Notch-dependent mouse T cell acute lymphoblastic leukemias cell lines, and the absence of Trib2 in a murine Trib2-knockout model was found to accelerate Notch1driven leukemias (Liang et al, 2016a;Stein et al, 2016). A correlation between Trib3 and Notch1 expression in lung adenocarcinoma cell lines led to work showing that Notch1 could be downregulated by the knockdown of Trib3 (Zhou et al, 2013).…”