Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia

Immunol Lett. 2010 May 4;130(1-2):115-24. doi: 10.1016/j.imlet.2009.12.007. Epub 2009 Dec 11.

Abstract

Constitutive MAPK signalling is observed in approximately 50% of acute myeloid leukaemia (AML) cases. JNK activation in particular is associated with treatment failure in AML. Tribbles proteins (trb-1, trb-2 and trb-3) are potent negative regulators of MAPK pathways influencing apoptosis, differentiation and cell-cycle progression. Here we aimed to examine tribbles gene expression in AML and to characterise their role in leukaemic cells. A microarray dataset was interrogated for tribbles expression levels in AML cases and healthy controls. Myeloid cell proliferation and apoptosis were assayed in response to trb-1/trb-2 gene knockdown and overexpression, as well as a physical and functional interaction between trb and C/EBPalpha. Trb-2 expression was reduced in AML compared to healthy controls (correlating with nucleophosmin (NPM1) mutations), while low trb-1 expression was associated with inactive C/EBPalpha. In vitro assays indicated that trb-1/trb-2 are growth restrictive and pro-apoptotic in Me-1 cells, each capable of inhibiting JNK activation. JNK inactivation was itself associated with reduced Bcl-2 Ser70 phosphorylation, a residue which, when phosphorylated, maintains the anti-apoptotic activity of Bcl-2. Consistent with this, tribbles-mediated dephosphorylation of Bcl-2 Ser70 was associated with subsequent apoptosis. Trb-1/trb-2 transcription appeared to be moderately C/EBPalpha-responsive, and physical interaction between C/EBPalpha and trb-1/trb-2 was observed, suggesting a potential for auto-regulation of trb-1 and trb-2 transcription. In conclusion, we propose that trb-1 and trb-2 tumour suppressor activity may be abrogated in a proportion of AML patients. This may lead to enhanced cell survival, and therefore contribute to pathogenesis of the disease. Trb-1/trb-2 may, therefore, represent useful therapeutic targets for the treatment of AML in patients with dys-regulated trb activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Blotting, Western
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Line, Tumor
  • Cells, Cultured
  • Child, Preschool
  • Down-Regulation*
  • Female
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukemia, Myeloid, Acute / metabolism*
  • Male
  • Protein Array Analysis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Young Adult

Substances

  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • TRIB1 protein, human
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • TRIB2 protein, human