The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer

Graner, Edgard; Tang, Dan; Rossi, Sabrina; A, Baron; Migita, Toshiro; Weinstein, Lisa J.; Lechpammer, Mirna; Huesken, Dieter; Zimmermann, Johann; Signoretti, Sabina; Loda, Massimo

doi:10.1016/s1535-6108(04)00055-8

Cited by 305 publications

(330 citation statements)

References 25 publications

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“…Allogeneic stem cell transplantation, with an HLA identical sister as a donor, was performed in June 1995. BM relapse occurred in March 2000, at which time the karyotype was 46,XY,t(4;6)(q24;p11),del(5)(q15),t(11;18)(q23;q21) [24]. The immunophenotype was essentially the same as at diagnosis.…”

Section: Case Historymentioning

confidence: 92%

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

et al. 2005

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Although many of the chromosomal abnormalities in hematologic malignancies are identifiable cytogenetically, some are only detectable using molecular methods. We describe a novel cryptic t(7;21)(p22;q22) in acute myeloid leukemia (AML). FISH, 3 0 RACE, and RT-PCR revealed a fusion involving RUNX1 and the ubiquitin-specific protease (USP) gene USP42. The genomic breakpoint was in intron 7 of RUNX1 and intron 1 of USP42. The reciprocal chimera was not detected -neither on the transcriptional nor on the genomic level -and FISH showed that the 5 0 part of USP42 was deleted. USP42 maps to a 7p22 region characterized by segmental duplications. Notably, 17 kb duplicons are present 1 Mb proximal to USP42 and 3 Mb proximal to RUNX1; these may be important in the genesis of t (7;21). This is the second cryptic RUNX1 translocation in hematologic malignancies and the first in AML. The USPs have not previously been reported to be rearranged in leukemias. The cellular context in which USP42 is active is unknown, but we here show that it is expressed in normal bone marrow, in primary AMLs, and in cancer cell lines. Its involvement in the t(7;21) suggests that deregulation of ubiquitin-associated pathways may be pathogenetically important in AML.

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Section: Case Historymentioning

confidence: 92%

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

et al. 2005

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“…Previous publications identified cyclin D1, mdm2 and fatty acid synthase as targets, which, upon de-ubiquitination from K48 chains and accumulation, promote cell cycle progression or render cells resistant to cell death. [37][38][39] Nevertheless, knockdown of USP2a is not causing apoptosis (Figure 1a, Supplementary Figure S1A). Thus, the effect of USP2a on apoptosis could depend on the cell death signal.…”

Section: Usp2a Mediates Cell Death By Tnf A-l Mahul-mellier Et Almentioning

confidence: 96%

De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF

Pazarentzos

Datler

et al. 2011

Cell Death Differ

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Components of the TNFR1 complex are subject to dynamic ubiquitination that impacts on their effects as signalling factors. We have found that the ubiquitin-specific protease USP2a has a pivotal role in the decision for cell death or survival by the TNFR1 complex. This enzyme is a novel component of the TNFR1 complex that is recruited upon ligand binding and controls the signalling activity of the TNFR1-interacting protein RIP1 by removing its K63-linked ubiquitin chains. USP2a similarly de-ubiquitinates TRAF2, a ubiquitin-ligase recruited to the TNFR1 complex. During the TNF response the activity of USP2a on RIP1 and TRAF2 is required for the efficient reappearance of IjBa, which is essential to inactivate the anti-apoptotic transcription factor NF-jB. The effects of USP2a culminate in the conversion of the anti-apoptotic TNFR1 complex I into the pro-apoptotic TNFR1 complex II. Consequently, downregulation of USP2a promotes NF-jB activation and protects cells against TNF-induced cell death. Tumour necrosis factor (TNF) is a pleiotropic cytokine that can, through the TNF receptor 1 (TNFR1), elicit various cellular responses ranging from inflammation, cell proliferation, cell survival to apoptosis. The interaction of this cytokine with TNFR1 results in the recruitment of the adaptor TRADD to its intracellular death domain. RIP kinase 1 (RIP1), the ubiquitin ligase TNF receptor-associated factor 2 (TRAF2), and the inhibitors of apoptosis cIAP1 and cIAP2 then associate in the so-called complex I. 1 Following its recruitment to the complex I, RIP1 is ubiquitinated mainly by K63 ubiquitin chains. 2-5 The E3 ubiquitin ligase TRAF2 was the first to be described as being responsible for K63 ubiquitination of RIP1 5-7 together with the lipid shingosine-1-phosphate. 8 Other publications have shown that cIAP1/2 can attach K63 ubiquitin chains to RIP1 [9][10][11][12] or that TRAF2 and cIAPs cooperate for the ubiquitination of RIP1 6,13,14 . These ubiquitin chains bind and associate the TAB/TAK (TAK1/TAB2/TAB3) and NEMO/IKK (IKKa, b, g) kinases complex. 3,4,12,15 By proximity, TAK1 activates IKKb by phosphorylation, which in turn phosphorylates IkBa to promote its K48-linked polyubiquitination and degradation by the proteasome. The antiapoptotic transcription factor NF-kB is then free to translocate to the nucleus and activate gene transcription leading to survival of the cells. 7,[15][16][17][18][19][20] Upon internalisation of the complex and in the absence of K63 ubiquitination, RIP1 is able to form the so-called complex II with FADD and pro-caspase-8 to initiate apoptosis. 1,16 Hence, ubiquitin conjugation has a crucial role in allowing cells to decide between cell death and survival in the TNF signalling cascade. Although a number of ubiquitin ligases, that presumably modify components of the TNFR1 complex, have been identified, so far only two de-ubiquitinating proteases have functionally been found in the TNF signalling pathway that impact on cell death, A20 and CYLD (cylindromatosis tumour suppressor). 21-24 A20 is a ...

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“…We have previously shown that USP2a can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination (Stevenson et al, 2007). USP2a has oncogenic properties and its overexpression can prevent apoptosis induced by chemotherapeutic agents (Graner et al, 2004;Priolo et al, 2006). USP2a knockdown results in increased p53 protein expression and upregulation of p53 target genes (Priolo et al, 2006;Stevenson et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…USP2a mRNA is expressed in a range of normal tissues, the highest level of expression being in the testis (Lin et al, 2001;Park et al, 2002;Gousseva and Baker, 2003). USP2a is overexpressed in prostate cancer (Graner et al, 2004). This is associated with a reduction in p53 target gene expression, suggesting that USP2a overexpression could contribute to tumourigenesis by repression of p53 (Priolo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

MdmX is a substrate for the deubiquitinating enzyme USP2a

et al. 2009

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It has previously been shown that ubiquitin-specific protease 2a (USP2a) is a regulator of the Mdm2/p53 pathway. USP2a binds to Mdm2 and can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination. Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2. Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. This correlates with the ability of wild-type USP2a to deubiquitinate MdmX. siRNA-mediated knockdown of USP2a in NTERA-2 testicular embryonal carcinoma cells and MCF7 breast cancer cells causes destabilization of MdmX and results in a decrease in MdmX protein levels, showing that endogenous USP2a participates in the regulation of MdmX stability. The therapeutic drug, cisplatin decreases MdmX protein expression. USP2a mRNA and protein levels were also reduced after cisplatin exposure. The magnitude and time course of USP2a downregulation suggests that the reduction in USP2a levels could contribute to the decrease in MdmX expression following treatment with cisplatin. Knockdown of USP2a increases the sensitivity of NTERA-2 cells to cisplatin, raising the possibility that suppression of USP2a in combination with cisplatin may be an approach for cancer therapy.

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The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer

Cited by 305 publications

References 25 publications

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF

MdmX is a substrate for the deubiquitinating enzyme USP2a

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