HRX Leukemic Fusion Proteins Form a Heterocomplex with the Leukemia-associated Protein SET and Protein Phosphatase 2A

Adler, Haskell T.; Nallaseth, Ferez S.; Walter, Gernot; Tkachuk, Denis

doi:10.1074/jbc.272.45.28407

Cited by 97 publications

(87 citation statements)

References 56 publications

(49 reference statements)

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“…In addition to its activity as an inhibitor of PP2A, SET is also a potent inhibitor of the tumour suppressor NM23-H1 (Fan et al, 2003). Notably, SET was described as part of a fusion gene with the nucleopore complex protein CAN in a patient with t(6;9)(p23;q34) acute myeloid leukaemia (AML) (Adachi et al, 1994), and it was found associated with the oncoprotein Mll (ALL1, HRX) in leukaemic cell lines (Adler et al, 1997). Thus, it is intuitive that genetic (mutations in the gene encoding a specific PP2A subunits) or functional (e.g.…”

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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“…These domains do not recognize a specific sequence but rather a structure of cruciform or bent DNA. The MLL AT-hook region was shown to interact with SET protein (not to be confused with SET domain), protein phosphatase 2A (PP2A), and the proapoptotic protein GADD34 [Adler et al, 1997;Adler et al, 1999]. MLL fusion proteins, but not the wild-type MLL, inhibit GADD34-induced apoptosis suggesting that this may be an important factor in MLL-associated leukemias [Adler et al, 1999].…”

Section: Many Pieces Of the Puzzlementioning

confidence: 99%

MLL: How complex does it get?

Popovic

Zeleznik‐Le

2005

J of Cellular Biochemistry

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The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain-and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered. J. Cell. Biochem. 95: 234-242, 2005. ß 2005 Wiley-Liss, Inc.

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“…It has been identified as a potent inhibitor of protein phosphatase 2A (Li et al, 1996;Adler et al, 1997;Pandey et al, 2003) and as a regulator of DNA replication, chromatin remodeling and gene transcription (Matsumoto et al, 1993;Okuwaki and Nagata, 1998;Shikama et al, 2000;Seo et al, 2001;Cervoni et al, 2002;Kutney et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity

et al. 2006

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We report here that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts in vitro and in vivo with the protein SET. This interaction is performed through the acidic domain of SET located at the carboxy terminal region. On analysing the functional relevance of SET-GAPDH interaction, we observed that GAPDH reverses in a dose-dependent manner, the inhibition of cyclin Bcdk1 activity produced by SET. Similarly to SET, GAPDH associates with cyclin B, suggesting that the regulation of cyclin B-cdk1 activity might be mediated not only by the interaction of GAPDH with SET but also with cyclin B. To analyse the putative role of GAPDH on cell cycle progression, HCT116 cells were transfected with a GAPDH expression vector. Results indicate that overexpression of GAPDH does not affect the timing of DNA replication but induces an increase in the number of mitosis, an advancement of the peak of cyclin B-cdk1 activity and an acceleration of cell cycle progression. All these results suggest that GAPDH might be involved in cell cycle regulation by modulating cyclin B-cdk1 activity.

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HRX Leukemic Fusion Proteins Form a Heterocomplex with the Leukemia-associated Protein SET and Protein Phosphatase 2A

Cited by 97 publications

References 56 publications

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

MLL: How complex does it get?

Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity

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