Abstract
The nuclear receptor co-repressor (N-CoR) is a key component of the generic co-repressor complex that plays an important role in the control of cellular growth and differentiation. As shown by us recently, the growth suppressive function of N-CoR largely relies on its capacity to repress Flt3, a key regulator of cellular gorwth during normal and malignant hematopoesis. We further demonstrated how de-repression of Flt3 due to the misfolded conformation dependent loss (MCDL) of N-CoR contributed to malignant growth in acute myeloid leukemia (AML). However, the molecular mechanism underlying the MCDL of N-CoR and its implication in AML pathogenesis is not fully understood. Here, we report that Akt-induced phosphorylation of N-CoR at the consensus Akt motif is crucial for its misfolding and subsequent loss in AML (AML-M5). N-CoR displayed significantly higher level of serine specific phosphorylation in almost all AML-M5 derived cells and was subjected to processing by AML-M5 specific aberrant protease activity. To identify the kinase linked to N-CoR phosphorylation, a library of activated kinases was screened with the extracts of AML cells; leading to the identification of Akt as the putative kinase linked to N-CoR phosphorylation. Consistent with this finding, a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells. Site directed mutagenic analysis of N-CoR identified serine 1450 as the crucial residue whose phosphorylation by Akt was essential for the misfolding and loss of N-CoR protein. Moreover, Akt-induced phosphorylation of N-CoR contributed to the de-repression of Flt3, suggesting a cross talk between Akt signaling and N-CoR misfolding pathway in the pathogenesis of AML-M5. The N-CoR misfolding pathway could be the common downstream thread of pleiotropic Akt signaling activated by various oncogenic insults in some subtypes of leukemia and solid tumors.
Highlights
Balanced transcriptional control maintained by the coordinated actions of co-activator and co-repressor proteins and sequence specific transcriptional factors play an important role in the normal growth and development of cells in the hematopoietic system [1]
We further demonstrated how deregulation of Flt3 due to a misfolded conformation dependent loss (MCDL) of nuclear receptor co-repressor (N-CoR) contributed to the malignant growth and transformation of cells in acute myeloid leukemia of the French– American–British (FAB)-M5 subtype (AML-M5) [11,12,13,14]
Given the key role of N-CoR in the transcriptional repression of Flt3 [11], we hypothesized that de-regulation of N-CoR mediated transcriptional control as a result of its misfolding might have a significant implication in the pathogenesis of AML
Summary
Balanced transcriptional control maintained by the coordinated actions of co-activator and co-repressor proteins and sequence specific transcriptional factors play an important role in the normal growth and development of cells in the hematopoietic system [1]. We identified N-CoR as a key component of the multiprotein repressor complex containing Ski, PML and HDAC proteins, and defined the crucial role of N-CoR in transcriptional repression mediated by the tumor suppressors Mad and Rb [8,9,10]. We identified an important role for N-CoR in the repression of Flt, a key regulator of cellular growth during normal and malignant hematopoesis [11]. We further demonstrated how deregulation of Flt due to a misfolded conformation dependent loss (MCDL) of N-CoR contributed to the malignant growth and transformation of cells in acute myeloid leukemia of the FAB-M5 subtype (AML-M5) [11,12,13,14]. Selective Akt activation was observed in multiple human primary AML-M5 cells but not in normal cells surrounding the malignant tissue, suggesting a key role of Akt in the pathogenesis of AML-M5 [18]
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