MOZ–TIF2-mediated destruction of CBP/p300 is blocked by calpain inhibitor 2

Kindle, Karin B.; Collins, Hilary M.; Heery, David M.

doi:10.1038/leu.2010.92

Cited by 4 publications

(3 citation statements)

References 8 publications

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“…However, calpains are known to target cell cycle-related proteins such as CDKs. 55, 56, 57, 58 As well, Kindle et al 59 have shown that calpain is essential for mediating the removal of the CBP/p300 acetyltransferases that are essential for MOZ-TIF2-mediated transformation in AML. Such proteins may therefore be important targets in AML.…”

Section: Discussionmentioning

confidence: 99%

Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression

Niapour

Farr

Minden

et al. 2012

Blood Cancer Journal

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Calpains are intracellular cysteine proteases that have crucial roles in many physiological and pathological processes. Elevated calpain activity has been associated with many pathological states. Calpain inhibition can be protective or lethal depending on the context. Previous work has shown that c-myc transformation regulates calpain activity by suppressing calpastatin, the endogenous negative regulator of calpain. Here, we have investigated calpain activity in primary acute myelogenous leukemia (AML) blast cells. Calpain activity was heterogeneous and greatly elevated over a wide range in AML blast cells, with no correlation to FAB classification. Activity was particularly elevated in the CD34+CD38− enriched fraction compared with the CD34+CD38+ fraction. Treatment of the cells with the specific calpain inhibitor, PD150606, induced significant apoptosis in AML blast cells but not in normal equivalent cells. Sensitivity to calpain inhibition correlated with calpain activity and preferentially targeted CD34+CD38− cells. There was no correlation between calpain activity and p-ERK levels, suggesting the ras pathway may not be a major contributor to calpain activity in AML. A significant negative correlation existed between calpain activity and calpastatin, suggesting calpastatin is the major regulator of activity in these cells. Analysis of previously published microarray data from a variety of AML patients demonstrated a significant negative correlation between calpastatin and c-myc expression. Patients who achieved a complete remission had significantly lower calpain activity than those who had no response to treatment. Taken together, these results demonstrate elevated calpain activity in AML, anti-leukemic activity of calpain inhibition and prognostic potential of calpain activity measurement.

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Section: Discussionmentioning

confidence: 99%

Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression

Niapour

Farr

Minden

et al. 2012

Blood Cancer Journal

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“…It has been shown that multiple inhibitors specific to HAT, such as p300 and CBP, suppress growth and induces apoptosis of multiple types of human cancers in vitro as well as tumors using the experimental mouse tumor models (31–34). Using a high-throughput screening approach, Chimenti et al recently identified the chemical cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH2) as a GCN5-specific inhibitor that suppresses the in vitro GCN5 catalytic activity and GCN5-mediated H3K9 acetylation in yeast and in human cancer cell lines (35).…”

Section: Discussionmentioning

confidence: 99%

The Histone Acetyltransferase GCN5 Expression Is Elevated and Regulated by c-Myc and E2F1 Transcription Factors in Human Colon Cancer

Yin

Jin²,

Zhao³

et al. 2015

gene expr

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The histone acetyltransferase GCN5 has been suggested to be involved in promoting cancer cell growth. But its role in human colon cancer development remains unknown. Herein we discovered that GCN5 expression is significantly upregulated in human colon adenocarcinoma tissues. We further demonstrate that GCN5 is upregulated in human colon cancer at the mRNA level. Surprisingly, two transcription factors, the oncogenic c-Myc and the proapoptotic E2F1, are responsible for GCN5 mRNA transcription. Knockdown of c-Myc inhibited colon cancer cell proliferation largely through downregulating GCN5 transcription, which can be fully rescued by the ectopic GCN5 expression. In contrast, E2F1 expression induced human colon cancer cell death, and suppression of GCN5 expression in cells with E2F1 overexpression further facilitated cell apoptosis, suggesting that GCN5 expression is induced by E2F1 as a possible negative feedback in suppressing E2F1-mediated cell apoptosis. In addition, suppression of GCN5 with its specific inhibitor CPTH2 inhibited human colon cancer cell growth. Our studies reveal that GCN5 plays a positive role in human colon cancer development, and its suppression holds a great therapeutic potential in antitumor therapy.

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“…This observation led to the proposition that abnormal histone acetylation driven by the fusion proteins might be at the origin of the leukemic transformation 12 , 13 . Alternatively, it has been proposed that the ability of MOZ-TIF2 to deplete CBP, particularly from the promyelocytic leukemia (PML) bodies, results in subversion of normal gene expression leading to development of leukemia 14 , 15 , 16 .…”

mentioning

confidence: 99%

Expression of the MOZ-TIF2 oncoprotein in mice represses senescence

Largeot

Pérez-Campo

Marinopoulou

et al. 2016

Experimental Hematology

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The MOZ-TIF2 translocation, which fuses monocytic leukemia zinc finger protein (MOZ) histone acetyltransferase (HAT) with the nuclear co-activator TIF2, is associated with the development of acute myeloid leukemia. We recently found that in the absence of MOZ HAT activity, p16INK4a transcriptional levels are significantly increased, triggering an early entrance into replicative senescence. Because oncogenic fusion proteins must bypass cellular safeguard mechanisms, such as senescence and apoptosis, to induce leukemia, we hypothesized that this repressive activity of MOZ over p16INK4a transcription could be preserved, or even reinforced, in MOZ leukemogenic fusion proteins, such as MOZ-TIF2. We describe here that, indeed, MOZ-TIF2 silences expression of the CDKN2A locus (p16INK4a and p19ARF), inhibits the triggering of senescence and enhances proliferation, providing conditions favorable to the development of leukemia. Furthermore, we describe that abolishing the MOZ HAT activity of the fusion protein leads to a significant increase in expression of the CDKN2A locus and the number of hematopoietic progenitors undergoing senescence. Finally, we report that inhibition of senescence by MOZ-TIF2 is associated with increased apoptosis, suggesting a role for the fusion protein in p53 apoptosis-versus-senescence balance. Our results underscore the importance of the HAT activity of MOZ, preserved in the fusion protein, for repression of the CDKN2A locus transcription and the subsequent block of senescence, a necessary step for the survival of leukemic cells.

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MOZ–TIF2-mediated destruction of CBP/p300 is blocked by calpain inhibitor 2

Cited by 4 publications

References 8 publications

Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression

Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression

The Histone Acetyltransferase GCN5 Expression Is Elevated and Regulated by c-Myc and E2F1 Transcription Factors in Human Colon Cancer

Expression of the MOZ-TIF2 oncoprotein in mice represses senescence

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