β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

Abstract

The expression of ␤-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic ␤-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic ␤-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic ␤-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. ␤-Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53 ؊/؊ mice. They are CD4 ؊ CD8؊ , while p53-dependent lymphomas are largely CD4 ؉ CD8 ؉ , and they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic ␤-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic ␤-catenin.Cells sense and respond to their environment via signaling cascades initiated at the cell surface. These signals are propagated by various mechanisms through the cytoplasm, ultimately resulting in the alteration of gene expression patterns in the nucleus. One such pathway is the canonical Wnt-␤-catenin-T-cell factor (TCF) pathway, which plays a causative role in cancers of the colon (17,23,25,28,61), breast (37, 48), and epidermal (18,26,43) tissues. Accordingly, tissue-specific expression of transgenic ␤-catenin can result in the development of aggressive tumors early in life (13,23,34). Briefly, the secreted extracellular Wnt glycoproteins bind to the Frizzled receptors on the surface of cells. This results in the release of ␤-catenin from a destruction complex, allowing it to accumulate in the cytoplasm. ␤-Catenin then travels to the nucleus, where it binds to the transcription factors TCF/lymphocyte enhancer binding factor to activate the transcription of target genes linked to cellular proliferation and cancer, including c-Myc and cyclin D1 (25, 61). Cancers involving stabilized ␤-catenin often deregulate the tumor suppressor p53, whose function normally impedes tumor formation by inducing growth arrest or apoptosis (24, 28). Thus, p53 appears to be an important impediment to ␤-catenin-induced tumorigenesis; however, the molecular mechanisms remain poorly understood.In the thymus, T-cell development is characterized by the expression of the cell surface markers CD4 and CD8 in the following order: double-negative cells (DN), double-positive cells (DP), and either CD4-or CD8-expressing single-positive (SP) cells that migrate out of the thymus into the periphery. The DN population is further divided into four subpopulations based on the cell surface expression of CD44 and/or CD25 into DN1, DN2, DN3, and DN4. At the DN2 and DN3 stages of development, thymocytes undergo RAG-dependent V(D)J rearrangements to generate the recombined T-cell receptor (TCR) ␤-chain. The generat...

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…Our study builds on previous work implicating β-catenin in the regulation of genome stability (Aoki et al, 2007;Dose et al, 2014) and in the DNA damage response (Chandra et al, 2015;Priolli et al, 2013;Tavana et al, 2013;Xu et al, 2008;Zhang et al, 2011). Indeed, our data align well with these previous reports.…”

“…β-Catenin (S33Y) expression resulted in an increase in the number of DNA lesions compared to the number in mock-transfected cells (Fig. 2D), as previously shown in thymocytes (Xu et al, 2008). Co-expression of constitutively active β-catenin with a Myc-tagged α-catenin partially alleviated the increase in the number of lesions (Fig.…”

β-Catenin induces T-cell transformation by promoting genomic instability

“…Uncontrolled β-catenin kills two birds with one stone as it simultaneously promotes survival and DNA damage. This seems to depend on the levels of β-catenin because models with moderate up-regulation of β-catenin develop lymphomas only when p53 is also ablated (36). Our model, based on constitutive activation of endogenous β-catenin, expresses high levels of β-catenin that evidently suffice to tip the balance toward transformation without the need for additional genetic manipulation.…”

Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice

“…Further understanding of how Parp-2 coordinates, repair, signalling and surveillance functions in response to intrinsic DNA damage during thymocyte development will provide further insights into the mechanisms underlying malignant transformation disorders. As loss of Parp-2 and p53 do not appear to be functionally equivalent, DNA damage is p53-independent whereas apoptosis is p53-dependent (Xu et al, 2008), and their simultaneous loss substantially accelerates tumorigenesis, our work highlights the potential importance of examining human tumours for the status of both genes. Interplay of Parp-2 and p53 in tumorigenesis L Nicolás et al…”