Suppression of p53 by Notch in Lymphomagenesis: Implications for Initiation and Regression

Abstract

Aberrant Notch signaling contributes to more than half of all human T-cell leukemias, and accumulating evidence indicates Notch involvement in other human neoplasms. We developed a tetracycline-inducible mouse model (Top-Notch ic

Acetylation controls Notch3 stability and function in T-cell leukemia

“…In agreement with our present observations and with previous data demonstrating that Notch signaling activation in pre-T cells or in bone marrow results in the accumulation of CD4 þ CD8 þ DP cells in spleen and lymph nodes (Pear et al, 1996;Beverly et al, 2005;Bellavia et al, 2007), this feature being a characteristic of T-cell leukemia, we observed a decreased Notch3 protein expression specifically in splenic CD4 þ CD8 þ DP cells of TSA-treated mice. Therefore, it may be speculated that, by impairing N3 IC signaling, HDACi block the expansion or migration of CD4 þ CD8 þ cells, possibly representing the precursors of leukemic cells, in peripheral lymphoid organs and in circulating blood.…”

Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1

“…Notch1 has been implicated in both differentiation and cell death and its expression is developmentally regulated in the thymus, suggesting that Notch1 may play a critical role in thymic development. Overactivation of Notch1 may play a role in tumorigenesis resulting from a loss of functional p53 (Beverly et al, 2005). In addition, NIC is abundant in human T-cell acute lymphoblastic leukemia, and a high level of NIC is associated with the attendant pathogenesis (Weng et al, 2004).…”

It's T-ALL about Notch

“…Suppression of the p53-mediated apoptotic response was demonstrated to be critical in Notch-induced leukemogenesis. In a mouse model of Notch-induced T-ALL, tumors express low levels of p53 protein without a reduction in mRNA levels (Beverly et al, 2005). This led investigators to hypothesize that Notch may regulate p53 by increasing its proteolytic degradation (Beverly et al, 2005).…”

“…In a mouse model of Notch-induced T-ALL, tumors express low levels of p53 protein without a reduction in mRNA levels (Beverly et al, 2005). This led investigators to hypothesize that Notch may regulate p53 by increasing its proteolytic degradation (Beverly et al, 2005). Disruption of mdm2-p53 association by nutlin or g-irradiation resulted in an increase in p53 protein levels, demonstrating that the mdm2-p53 mechanism is functional in Notch-induced T-ALL tumors.…”

“…Disruption of mdm2-p53 association by nutlin or g-irradiation resulted in an increase in p53 protein levels, demonstrating that the mdm2-p53 mechanism is functional in Notch-induced T-ALL tumors. However, levels of ARF protein are undetectable and examination of the ARF locus revealed that it is intact, indicating that Notch regulates ARF (Beverly et al, 2005). This suggests the possibility that Notch suppresses p53 by inhibiting ARF leading to continuous mdm2-induced degradation of p53 by the proteosome.…”