The p53-Binding Protein 53BP2 Also Interacts with Bcl2 and Impedes Cell Cycle Progression at G<sub>2</sub>/M

Naumovski, Louie; Cleary, Michael L.

doi:10.1128/mcb.16.7.3884

Cited by 149 publications

(134 citation statements)

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“…Although recent studies have (Liu et al, 2004;Zhang et al, 2005), our results describe for the first time that a significant percentage of patients with ALL have a decreased expression of ASPP1; that lack of expression is due to hypermethylation of the gene promoter and, more importantly, that hypermethylation and downregulation of ASPP1 expression is, significantly and independently of other prognostic factors, associated with poor prognosis with a reduced DFS and OS both in children and adult ALL. The initial isolation of ASPP1 and ASPP2 proteins was performed based on two hybrid screening systems using p53 and bcl-2 as baits (Iwabuchi et al, 1994;Naumovski and Cleary, 1996). These studies identified two proteins 53BP2 and Bbp that are now recognized as truncated forms of ASPP2 (C-terminal 529 amino acids and the truncation of 123 amino acid at the N-terminal, respectively).…”

Section: Discussionmentioning

confidence: 99%

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

et al. 2006

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We have analyzed the regulation and expression of ASPP members, genes implicated in the regulation of the apoptotic function of the TP53 tumor-suppressor gene, in acute lymphoblastic leukemia (ALL). Expression of ASPP1 was significantly reduced in ALL and was dependent on hypermethylation of the ASPP1 gene promoter. Abnormal ASPP1 expression was associated with normal function of the tumor-suppressor gene TP53 in ALL. The analyses of 180 patients with ALL at diagnosis showed that the ASPP1 promoter was hypermethylated in 25% of cases with decreased mRNA expression. Methylation was significantly higher in adult ALL vs childhood ALL (32 vs 17%, P ¼ 0.03) and T-ALL vs B-ALL (50 vs 9%, P ¼ 0.001). Relapse rate (62 vs 44%, P ¼ 0.05) and mortality (59 vs 43%, P ¼ 0.05) were significantly higher in patients with methylated ASPP1. DFS and OS were 32.8 and 33.7% for patients with unmethylated ASPP1 and 6.1 and 9.9% for methylated patients (Po0.001 y Po0.02, respectively). On the multivariate analysis, methylation of the ASPP1 gene promoter was an independent poor prognosis factor in ALL patients. Our results demonstrate that decreased expression of ASPP1 in patients with ALL is due to an abnormal methylation of its promoter and is associated with a poor prognosis.Oncogene ( Mutations of TP53 may result in an inhibition of protein function, which is associated with tumor progression and genetic instability (Caron de Fromentel and Soussi, 1992;Hollstein et al., 1994;Soussi et al., 1994). Although 40-50% of human tumors have mutations on TP53, the percentage of mutations in patients with leukemia is significantly lower (less that 10%), suggesting that other mechanisms may be involved in the inability of p53 to induce apoptosis since p53 does not suppress tumor growth or induce apoptosis in tumors with wild-type TP53.The recently described ASPP family of proteins comprised of ASPP1, ASPP2 and iASPP has been implicated in the apoptotic function of TP53 and p53 family members TP73L (p63) and TP73 (Bergamaschi et al., 2004). Different studies have shown that ASPP1 and ASPP2 increase the apoptotic effect of p53 by inducing the transcription of proapoptotic genes such as BAX and PIG3 mediated by TP53, while they have no influence on the transcription of MDM2 and CDKN1A (p21, Cip1), which mediate p53-dependent cell cycle arrest (Samuels-Lev et al., 2001;Slee and Lu, 2003;Bergamaschi et al., 2004). Transactivation of TP53-mediated transcription of proapoptotic genes mediated by ASPP1 and ASPP2 is completely abolished by increased expression of the evolutionary conserved TP53 inhibitor and third member of the ASPP family, iASPP (Bergamaschi et al., 2003).It has been hypothesized that in wild-type TP53 tumors, alterations of ASPP1 and/or ASPP2, can produce a selective advantage due to the lack of stimulation of apoptosis (Samuels-Lev et al., 2001;Slee and Lu, 2003;Bergamaschi et al., 2004). Samuels-Lev et al. (2001) These two authors contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

et al. 2006

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“…The ANK domains in the p53-binding protein 53BP2 and in the cytoskeletal protein ankyrin are known to bind to diverse partners. More specifically, 53BP2 binds to p53, Bcl2, and the catalytic subunit of the protein phosphatase PP1 (23,24), whereas ankyrin binds to at least seven distinct membrane proteins (referenced in Ref. 25).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Sbodio

Wen

2002

Journal of Biological Chemistry

145

149

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Tankyrase-1 and -2 are closely related poly(ADP-ribose) polymerases that use an ankyrin-repeat domain to bind diverse proteins, including TRF (telomere-repeat binding factor)-1, IRAP (insulin-responsive aminopeptidase), and TAB182 (182-kDa tankyrase-binding protein). TRF1 binding allows tankyrase to regulate telomere dynamics in human cells, whereas IRAP binding presumably allows tankyrase to regulate the targeting of IRAP. The mechanism by which tankyrase binds to diverse proteins has not been investigated. Herein we describe a novel RXXPDG motif shared by IRAP, TAB182, and human TRF1 that mediates their binding to tankyrases. Interestingly, mouse TRF1 lacks this motif and thus does not bind either tankyrase-1 or -2. Using the ankyrin domain of tankyrase as a bait in a yeast two-hybrid screen, we also found the RXXPDG motif in six candidate tankyrase partners, including the nuclear/mitotic apparatus protein (NuMA). We verified NuMA as an RXXPDG-mediated partner of tankyrase and suggest that this interaction contributes to the known colocalization of tankyrase and NuMA at mitotic spindle poles.

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“…For example, FLIP is up-regulated through NF-B activation, resulting in increased resistance to TNF-␣ (24). Bcl2 and p53 binding protein (BBP/53BP2) is a DNA damage-inducible protein which functions to promote apoptosis upon DNA damage (25,26). IEX-1L antideath protein has been recognized as an apoptosis inhibitor involved in NF-B-mediated cell survival (15,16).…”

Section: Expression Profiling Of Tnf-␣-modulated Nf-b-dependent Genesmentioning

confidence: 99%

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa

Nagaki

Banno

et al. 2003

The Journal of Immunology

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Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-α and also depend on NF-κB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-α-induced apoptosis in Hc cells expressing a mutant form of IκB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-α and accelerated TNF-α-induced apoptosis in IκB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-α-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-κB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-α-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-α-induced hepatocyte apoptosis.

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The p53-Binding Protein 53BP2 Also Interacts with Bcl2 and Impedes Cell Cycle Progression at G₂/M

Cited by 149 publications

References 55 publications

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

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The p53-Binding Protein 53BP2 Also Interacts with Bcl2 and Impedes Cell Cycle Progression at G2/M

Cited by 149 publications

References 55 publications

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

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The p53-Binding Protein 53BP2 Also Interacts with Bcl2 and Impedes Cell Cycle Progression at G₂/M