Genetic Imbalances in Preleukemic Thymuses

Verlaet, Myriam; Deregowski, Valérie; Denis, Gerald V.; Humblet, Chantal; Stalmans, Marie-Thérèse; Castronovo, Vincenzo; Boniver, Jacques; Defresne, Marie-Paule

doi:10.1006/bbrc.2001.4731

Cited by 15 publications

(11 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The accumulated stathmin, regulated by MG-132, is a major cytosolic phosphoprotein constituent in leukemia cells and a main target of the Raf/MEK/ERK kinase cascade (Melhem et al, 1997;Lovric et al, 1998), playing important roles in cell growth (Melhem et al, 1997). We observed the upregulations of profilin1 and high mobility group protein 1, which were both mentioned in preleukemic thymuses and related to alterations of cell cycle and apoptosis (Verlaet et al, 2001;Witke et al, 2001). Heatshock protein 27, upregulated by MG-132 (Table 1) (Ito et al, 2002), was found to correlate with the susceptibility to carcinoma development (Soldes et al, 1999).…”

Section: Proteomic Analysis Of Ubiquitin-proteasome Effectsmentioning

confidence: 55%

Proteomic analysis of ubiquitin-proteasome effects: insight into the function of eukaryotic initiation factor 5A

Jin

Wang

et al. 2003

Oncogene

View full text Add to dashboard Cite

The global effect of ubiquitin-proteasome (UP) inhibitors on leukemic cell proteome was analysed. A total of 39 protein spots, affected by UP inhibitors, were identified, including 11 new apoptosis-associated proteins. They are involved in different cellular functions and four were associated with caspase-3 activation. Eukaryotic initiation factor 5A (eIF-5A) was identified in two spots; however, the peptide mass-fingerprinting for the accumulated one included a peptide with lysine 50 , indicating that hypusine formation was suppressed during UP inhibitor-induced apoptosis. Hypusine modification ensues immediately following translation of eIF-5A precursor, unless cells are treated with the modification inhibitors diaminoheptane. However, UP inhibitors induced a much stronger accumulation of unmodified eIF-5A compared to the effect of diaminoheptane. We further showed the unmodified eIF-5A was regulated in a proteasome-dependent manner. Inhibition of hypusine formation by diaminoheptane triggered apoptosis, but of particular interest is the finding that eIF-5A expression inhibition by antisense oligodeoxynucleotides significantly enhanced the stimulating effect of GM-CSF on cell growth. Therefore, the eIF-5A accumulation played important roles in the apoptosis induced by UP inhibitors. Moreover, hypusine inhibition in apoptosis was further revealed to be associated with the subcellular localization of eIF-5A. Our data pave the way to a better understanding of the mechanisms by which UP system has been linked to apoptosis.

show abstract

Section: Proteomic Analysis Of Ubiquitin-proteasome Effectsmentioning

confidence: 55%

Proteomic analysis of ubiquitin-proteasome effects: insight into the function of eukaryotic initiation factor 5A

Jin

Wang

et al. 2003

Oncogene

View full text Add to dashboard Cite

show abstract

“…However, few data to date implicate PABP in tumorigenesis. In the early stages of cancer, an increase of cellular PABP level was observed, suggesting a link between growth control and PABP level (50). Here, the novel interaction of PABP with the tumor suppressor BRCA1 protein provides new elements to implicate PABP in malignancy.…”

Section: Discussionmentioning

confidence: 80%

BRCA1 Interacts with Poly(A)-binding Protein

Dizin

Gressier

Magnard

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

BRCA1 has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair, cell cycle control, and apoptosis. We identified poly(A)-binding protein 1 (PABP) as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed the interaction by in vitro assays and coimmunoprecipitation in mammalian cells. Endogenous interaction between BRCA1 and PABP was also observed. This interaction was abolished by BRCA1 cancer-associated mutations, suggesting that it may be physiologically relevant. Deletion mapping demonstrated that the RNA recognition motifs 1-4 region of PABP is required to mediate the interaction with BRCA1. To understand the biological function of the BRCA1-PABP complex, we sought to determine whether BRCA1 is a modulator of translation. We showed here that inhibition of endogenous BRCA1 using a small interfering RNAbased approach decreased protein synthesis. Conversely, overexpression of BRCA1 activated translation. Using a RNA transfection approach, we clearly showed that BRCA1 modulates translation, independently of any transcriptional activity. The data presented here suggest that BRCA1 modulates protein synthesis via its interaction with PABP, providing a novel mechanism by which BRCA1 may exert its tumor suppressor function.The breast cancer susceptibility gene breast cancer 1 (BRCA1) acts as a tumor suppressor gene (1). Germ-line mutations of BRCA1 are found in about 40% of patients with inherited breast cancer and up to 90% of families with breast and ovarian cancer (2). The decreased BRCA1 expression found in approximately one-third of sporadic breast tumors may also play a role in these cancers (3, 4). Several lines of approach tend to define the biochemical function of BRCA1 protein. BRCA1 has thus far been involved in regulation of cell cycle checkpoints, apoptosis, DNA damage repair, transcription, and ubiquitination (5). Although the implication of BRCA1 in these cellular processes has been demonstrated, the exact mechanism of BRCA1 function remains unclear.The BRCA1 protein contains a RING finger at its N-terminal region (1), two nuclear export signals near its N terminus (6, 7), two nuclear localization signals in the central portion of the protein (8), and a tandem of two BRCT domains at its C-terminal region (9 -11). The majority of cancer-associated BRCA1 mutations affect the BRCT tandem, resulting in truncated products lacking one or two BRCT domains (2). These findings together with the observation that deletion of the Brca1 BRCT domains is responsible for tumor development in mice (12) demonstrate that BRCT domains play a central role in the BRCA1 tumor suppressor function.Several proteins interact with this region and collaborate functionally with BRCA1. For example, BRCA1 interacts with proteins implicated in transcriptional regulation such as RNA polymerase holoenzyme, CtIP (13-15), and histone deacetylases (16), with BACH1 implicated in response to DNA damage (17) and with acetyl-CoA carboxylase ␣ implicated in fatty acid syn...

show abstract

“…Moreover, high PABP levels interfere with maturation-specific deadenylation and translational inactivation of maternal mRNAs in Xenopus oocytes (Wormington et al, 1996). In addition, elevated PABP levels have been detected in early stages of cancer supporting a link between cell growth and PABP levels (Verlaet et al, 2001). In contrast, depletion of PABP from a cell-free extract prevents the initiation of mRNA translation, because PABP mediates mRNA circularization through binding to the eIF4F translation initiation complex, which enhances translation by facilitating the recycling of ribosomes (Kahvejian et al, 2005).…”

Section: Discussionmentioning

confidence: 95%

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

314

320

View full text Add to dashboard Cite

Tight control of translation is fundamental for eukaryotic cells, and deregulation of proteins implicated contributes to numerous human diseases. The neurodegenerative disorder spinocerebellar ataxia type 2 is caused by a trinucleotide expansion in the SCA2 gene encoding a lengthened polyglutamine stretch in the gene product ataxin-2, which seems to be implicated in cellular RNA-processing pathways and translational regulation. Here, we substantiate a function of ataxin-2 in such pathways by demonstrating that ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6, a component of P-bodies and stress granules, representing cellular structures of mRNA triage. We discovered that altered ataxin-2 levels interfere with the assembly of stress granules and cellular P-body structures. Moreover, ataxin-2 regulates the intracellular concentration of its interaction partner, the poly(A)-binding protein, another stress granule component and a key factor for translational control. Thus, our data imply that the cellular ataxin-2 concentration is important for the assembly of stress granules and P-bodies, which are main compartments for regulating and controlling mRNA degradation, stability, and translation. INTRODUCTIONAn essential step in the control of global gene expression in eukaryotes is the regulation of mRNA translation and degradation. Shortening of the poly(A) tail is the initial step to trigger mRNA for decay in two major mRNA degradation pathways in eukaryotic cells (Bernstein and Ross, 1989;Peltz et al., 1991;Decker and Parker, 1994;Beelman and Parker, 1995). In one pathway, the deadenylated mRNA is degraded by a cytoplasmic protein complex, the exosome, consisting of a number of exonucleases with 3Ј-5Ј activity (Butler, 2002). In the other pathway, shortening of the poly(A) tail leads to the removal of the cap structure of the mRNA by the decapping proteins DCP1 and DCP2 facilitating 5Ј-3Ј degradation of the mRNA through the exoribonuclease XRN1 (Beelman and Parker, 1995;Butler, 2002). These proteins colocalize in discrete cytoplasmic foci in mammalian cells, termed processing bodies or P-bodies (also known as DCP1-or GW182-bodies), indicating that mRNA decay is restricted to distinct cytoplasmic compartments in mammalian cells (van Dijk et al., 2002;Cougot et al., 2004). The human protein CCR4, which is involved in mRNA deadenylation, the decapping stimulating LSm proteins LSm1-7, the DEAD/Hbox RNA helicase DDX6 (also known as RCK/p54), GW182, and Ge-1 are components of P-bodies (Bouveret et al., 2000;Eystathioy et al., 2002;Ingelfinger et al., 2002; LykkeAndersen, 2002;Cougot et al., 2004;Yu et al., 2005). Moreover, the RNA-associated protein 55, hEDC3, Hedls as well as factors of the RISC complex localize to P-bodies in mammalian cells (Fenger-Gron et al., 2005;Liu et al., 2005;Sen and Blau, 2005;Yang et al., 2006). P-bodies represent dynamic structures that are in an equilibrium with polysomes and contain nontranslating mRNA . Remarkably, recent work demonstrated that mRNA molecules entering P-bodies can a...

show abstract

Genetic Imbalances in Preleukemic Thymuses

Cited by 15 publications

References 39 publications

Proteomic analysis of ubiquitin-proteasome effects: insight into the function of eukaryotic initiation factor 5A

Proteomic analysis of ubiquitin-proteasome effects: insight into the function of eukaryotic initiation factor 5A

BRCA1 Interacts with Poly(A)-binding Protein

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Contact Info

Product

Resources

About