Tumor suppressors BTG1 and BTG2: Beyond growth control

Abstract

Since the identification of B-cell translocation gene 1 (BTG1) and BTG2 as antiproliferation genes more than two decades ago, their protein products have been implicated in a variety of cellular processes including cell division, DNA repair, transcriptional regulation and messenger RNA stability. In addition to affecting differentiation during development and in the adult, BTG proteins play an important role in maintaining homeostasis under conditions of cellular stress. Genomic profiling of B-cell leukemia and lymphoma has put BTG1 and BTG2 in the spotlight, since both genes are frequently deleted or mutated in these malignancies, pointing towards a role as tumor suppressors. Moreover, in solid tumors, reduced expression of BTG1 or BTG2 is often correlated with malignant cell behavior and poor treatment outcome. Recent studies have uncovered novel roles for BTG1 and BTG2 in genotoxic and integrated stress responses, as well as during hematopoiesis. This review summarizes what is currently known about the roles of BTG1 and BTG2 in these and other cellular processes. In addition, we will highlight the molecular mechanisms and biological consequences of BTG1 and BTG2 deregulation during cancer progression and elaborate on the potential clinical implications of these findings.

Keywords: B-cell malignancies; BTG1; BTG2; antiproliferation; tumor suppressor.

Figure 1

Domains and interaction partners of BTG1 and BTG2. The conserved core of BTG1 and BTG2, known as the APRO domain, contains three smaller motifs, known as box A, box B, and box C. These boxes facilitate interactions with various protein partners. An additional LxxLL motif, which is required for binding to nuclear receptors, is also found in BTG1 and BTG2. BTG: B‐cell translocation gene; CAF1, CCR4‐associated factor 1; PRMT1, protein arginine methyltransferase I [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Major biological processes regulated by BTG1 and BTG2. Five major biological processes regulated by BTG1 and BTG2. Cell cycle: BTG1 and BTG2 expression induce cell cycle arrest at the G1 stage. BTG2 also facilitates DNA damage‐induced G2/M arrest. Differentiation: BTG1 and BTG2 expression are crucial for the differentiation of various tissues such as neurons and axial skeleton. Genotoxic stress: DNA damage can lead to programmed cell death via BTG1 and BTG2, in‐or dependent of p53. Integrated stress response: BTG1, together with PRMT1, promotes ATF4‐mediated cellular stress adaptation. BTG2 is a downstream effector of ROS and NF‐κB to overcome oxidative stress. Hematopoiesis: BTG1 acts as downstream effector of HLX, FOXO3a, and PAX5 to regulate the differentiation of hematopoietic, erythroid and B‐cells progenitors, respectively. BTG2 is involved in the differentiation of B cells and thymocyte progenitors. ATF4: activating transcription factor 4; BTG: B‐cell translocation gene; HLX: H2.0‐like homeobox; NF‐κB: nuclear factor‐κB; ROS: reactive oxygen species [Color figure can be viewed at wileyonlinelibrary.com]