CITED2 affects leukemic cell survival by interfering with p53 activation

Cell Death & Disease
Katharina MattesH Schepers

Abstract

CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) is a regulator of the acetyltransferase CBP/p300 and elevated CITED2 levels are shown in a number of acute myeloid leukemia (AML). To study the in vivo role of CITED2 in AML maintenance, AML cells were transduced with a lentiviral construct for RNAi-mediated knockdown of CITED2. Mice transplanted with CITED2-knockdown AML cells (n=4) had a significantly longer survival compared to mice transplanted with control AML cells (P<0.02). In vitro, the reduction of CITED2 resulted in increased p53-mediated apoptosis and CDKN1A expression, whereas BCL2 levels were reduced. The activation of p53 upon CITED2 knockdown is not a direct consequence of increased CBP/p300-activity towards p53, since no increased formation of CBP/p300/p53 complexes was demonstrated and inhibition of CBP/p300-activity could not rescue the phenotype of CITED2-deficient cells. Instead, loss of CITED2 had an inhibitory effect on the AKT-signaling pathway, which was indicated by decreased levels of phosphorylated AKT and altered expression of the AKT-pathway regulators PHLDA3 and SOX4. Notably, simultaneous upregulation of BCL2 or downregulation of the p53-target gene PHLDA3 rescued the apoptotic ph...Continue Reading

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Citations

Jul 18, 2019·The Journal of Pathology·Jakob HofvanderFredrik Mertens
Jul 31, 2020·World Journal of Clinical Oncology·Mónica T FernandesJosé Bragança
Apr 1, 2021·American Journal of Respiratory Cell and Molecular Biology·Sofia C WijkMattias Magnusson

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Methods Mentioned

BETA
acetylation
co-immunoprecipitation
co-IP
density gradient centrifugation
FCS
FACS
PCR
flow cytometry
exome sequencing

Software Mentioned

FlowJo
Image Lab
CFX Manager

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