Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia.
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.
Gilby
Daniel C
DC
Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
Sung
Hye Youn
HY
Winship
Peter R
PR
Goodeve
Anne C
AC
Reilly
John T
JT
Kiss-Toth
Endre
E
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D000090243:Nucleophosmin; D040081:Protein Array Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; C000716967:NPM1 protein, human; D012333:RNA, Messenger; C493170:TRIB1 protein, human; D000090243:Nucleophosmin; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human