Role of Protein Phosphatase 4 Regulatory Subunits in Myeloid Leukaemia


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Mirna Mourtada-Maarabouni1,Robert Hanson1,Cyntura Sivanandan1,Alicja Ladna1
1Keele University

Abstract

Background

The serine/ threonine protein phosphatase 4 (PP4) has been identified to play a role in apoptosis and tumorigenesis. The PP4 holoenzyme consists of PP4 catalytic subunit (PP4c) which interacts with four different regulatory subunits (PP4R1, PP4R2, PP4R3, PP4R4). Our previous studies showed that PP4c has an important tumour suppressor function and plays an important role in the control of cell death and survival of myeloid leukemic cells. The present work examines the role of PP4 regulatory subunits in myeloid leukaemia and investigates the involvement of PP4 regulatory subunits in mediating the effects of PP4c on myeloid leukemic cells.

Method

The human chronic myelogenous leukaemia K562 and promyelocytic leukemia HL60 cells were transfected with siRNAs to different PP4 regulatory subunits sequences and controls received scrambled siRNA. Cell viability, apoptosis, long term survival and cell cycle were assessed. 48 h post-transfection, control cells and cells transfected with PP4 regulatory subunits siRNAs were transiently transfected with pcDNA3.1-PP4c expression construct or pcDNA3.1. Cell viability and apoptosis level were assessed post transfection.

Results

Down-regulation of PP4R2, PP4R3 had no effects on cell survival. However, down-regulation of PP4R1 and PP4R4 greatly affected the survival and proliferation rate of myeloid leukemic cells. Over-expression of PP4c in cells transfected with (-) siRNA caused 50% reduction in viability compared to cells transfected with empty vector. Over-expression of PP4c in cells transfected with PP4 regulatory subunits siRNAs also showed 50% reduction in viability compared to cells transfected with empty vector.

Conclusion

PP4R1 and PP4R4 regulate the cell survival and cell proliferation in myeloid leukemic cells. Induction of cell death by over-expression of PP4c is not mediated by its interaction with PP4 regulatory subunits. The results suggest that dysfunction of the PP4 regulatory subunits as well as PP4 catalytic subunit may be important in the development and progression of myeloid leukaemia.

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