CIP2A is over-expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation.
ABSTRACT CIP2A is a newly identified inhibitor of PP2A. It can stabilize c-Myc and promote anchorage-independent cell growth and tumour formation. CIP2A is over-expressed in some solid tumours although its expression in acute myeloid leukaemia (AML) is still unknown.
CIP2A mRNA and protein expressions were determined in bone marrow mononuclear cells of both patients with AML and healthy controls using reverse transcription polymerase chain reaction and Western blot, respectively. We used siRNA to knock-down CIP2A expression in HL60 cells and then examined its potential roles during the pathological progression of AML.
CIP2A mRNA was present in 54 of 70 (77.14%) patients with newly diagnosed AML and in 11 of 14 (70.86%) patients with relapsed AML, which was significantly higher than complete remission specimens and healthy controls (P<0.001). Knock-down of CIP2A in HL60 cells slowed down cell proliferation, decreased clonogenic activity and promoted cell differentiation.
These results suggest that CIP2A is over-expressed in patients with newly diagnosed/relapsed AML and the expression of CIP2A could have potential use as a clinical marker for AML relapse after treatment. The high expression of CIP2A in HL60 cells may be related to active cell proliferation and arrest of cell differentiation. This study may shed light on the molecular function of CIP2A in myeloid leukemogenesis.
Article: CIP2A promotes proliferation of spermatogonial progenitor cells and spermatogenesis in mice.[show abstract] [hide abstract]
ABSTRACT: Protein phosphatase 2A (PP2A) is a critical regulator of protein serine/threonine phosphorylation. However, the physiological and developmental roles of different PP2A complexes are very poorly understood. Here, we show that a newly characterized PP2A inhibitory protein CIP2A is co-expressed with ki-67 and with self-renewal protein PLZF in the spermatogonial progenitor cell (SPC) population in the testis. CIP2A and PLZF expression was shown also to correlate Ki-67 expression in human testicular spermatogonia. Functionally, CIP2A mutant mouse testes exhibited smaller number of PLZF-positive SPCs and reduced sperm counts. Moreover, seminiferous tubuli cells isolated from CIP2A mutant mice showed reduced expression of Plzf and other renewal genes Oct-4 and Nanog at mRNA level. However, PLZF-deficient testes did not show altered CIP2A expression. Importantly, spermatogonia-specific restoration of CIP2A expression rescued PLZF expression and sperm production defects observed in CIP2A mutant mice. Taken together, these results reveal first physiological function for an emerging human oncoprotein CIP2A, and provide insights into maintenance of PLZF-positive progenitors. Moreover, demonstration that CIP2A expression can be systematically inhibited without severe consequences to normal mouse development and viability may have clinical relevance regarding targeting of oncogenic CIP2A for future cancer therapies.PLoS ONE 01/2012; 7(3):e33209. · 4.09 Impact Factor
Article: ETS1 mediates MEK1/2-dependent overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in human cancer cells.[show abstract] [hide abstract]
ABSTRACT: EGFR-MEK-ERK signaling pathway has an established role in promoting malignant growth and disease progression in human cancers. Therefore identification of transcriptional targets mediating the oncogenic effects of the EGFR-MEK-ERK pathway would be highly relevant. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized human oncoprotein. CIP2A promotes malignant cell growth and is over expressed at high frequency (40-80%) in most of the human cancer types. However, the mechanisms inducing its expression in cancer still remain largely unexplored. Here we present systematic analysis of contribution of potential gene regulatory mechanisms for high CIP2A expression in cancer. Our data shows that evolutionary conserved CpG islands at the proximal CIP2A promoter are not methylated both in normal and cancer cells. Furthermore, sequencing of the active CIP2A promoter region from altogether seven normal and malignant cell types did not reveal any sequence alterations that would increase CIP2A expression specifically in cancer cells. However, treatment of cancer cells with various signaling pathway inhibitors revealed that CIP2A mRNA expression was sensitive to inhibition of EGFR activity as well as inhibition or activation of MEK-ERK pathway. Moreover, MEK1/2-specific siRNAs decreased CIP2A protein expression. Series of CIP2A promoter-luciferase constructs were created to identify proximal -27 to -107 promoter region responsible for MEK-dependent stimulation of CIP2A expression. Additional mutagenesis and chromatin immunoprecipitation experiments revealed ETS1 as the transcription factor mediating stimulation of CIP2A expression through EGFR-MEK pathway. Thus, ETS1 is probably mediating high CIP2A expression in human cancers with increased EGFR-MEK1/2-ERK pathway activity. These results also suggest that in addition to its established role in invasion and angiogenesis, ETS1 may support malignant cellular growth via regulation of CIP2A expression and protein phosphatase 2A inhibition.PLoS ONE 01/2011; 6(3):e17979. · 4.09 Impact Factor