p73 can suppress the proliferation of cells that express mutant p53

Willis, Amy; Pipes, Tara; Zhu, Jianhui; Chen, Xinbin

doi:10.1038/sj.onc.1206505

Cited by 26 publications

(27 citation statements)

References 72 publications

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“…72,73 Importantly, TAp73 can mediate apoptosis independent of functional p53 74,75 and can sensitize p53-deficient tumors to chemotherapy. [76][77][78][79] In line with these observations, we showed that the cytotoxic activity of various anticancer drugs, such as F-ara-A, was enhanced for CLL cells following CD40 ligation, particularly for CLL cells that lacked functional p53. Specific blocking of c-Abl tyrosine kinase, a kinase that stabilizes TAp73 by phosphorylation, 80,81 inhibited the capacity of CD40 ligation to induce high-level expression of TAp73 as well as Bid.…”

Section: Improving the Capacity Of Cll To Function As Effective Antigsupporting

confidence: 67%

Cellular immune therapy for chronic lymphocytic leukemia

Kater

Oers

Kipps

2007

Blood

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Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for chemotherapyresistant leukemia-cell subclones. Cellular immune therapy promises to mitigate these complications and potentially provide for curative treatment. Most experience with this is in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), in which graft-versus-leukemia (GVL) effects can be observed and shown responsible for long-term disease-free survival. However, use of allo-HSCT for CLL is limited because of the lack of suitable donors and the treatment-related morbidity/mortality for elderly patients, who constitute the majority at risk for developing this disease. The GVL effect, however, suggests there are specific CLL-associated antigens that could be targeted in autologous cellular immune therapy. Effective strategies for this will have to overcome the disease-related acquired immune deficiency and the capacity of the leukemia-cell to induce T-cell tolerance, thereby compromising the activity of even conventional vaccines in patients with this disease. We will discuss the different strategies being developed to overcome these limitations that might provide for effective cellular immune therapy of CLL. IntroductionChronic lymphocytic leukemia (CLL) is a CD5 ϩ B-cell malignancy that is considered incurable. Historically, the first-line treatment consisted of alkylating agents, which resulted in response rates in up to 70% of patients, but did not improve survival. 1 Treatment regimens with the nucleoside (purine) analogs, such as fludarabine monophosphate (F-ara-A) or pentostatin, were found to yield higher response rates and to provide for longer progression-free survival, 2 especially in combination with cyclophosphamide. 3 However, despite effecting increased complete response rates, treatment with purine analogs alone does not appear to improve survival. 2 Newer treatment combinations have incorporated use of monoclonal antibodies to chemotherapy. 4,5 Although treatment with such combinations might provide for a first-time-observed survival benefit, 6 such therapy still is not considered curative.Although most patients initially respond to these chemotherapeutic approaches, many develop therapy-resistant disease with repeated therapy. Patients with refractory disease more frequently have leukemia cells that harbor deletions in the short arm of chromosome 17 (17pϪ), which often is associated with loss of functional p53, or in the long arm of chromosome 11 (11qϪ) in and/or around the gene encoding the ataxia telangectasia (ATM), which is a kinase required for p53 function. 7,8 Moreover, many chemotherapy-refractory patients have leukemia cells that have lost functional p53. Because the cytoreductive activity of most chemotherapy agents requires functional p53, 9,10 loss of p53 is ...

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Section: Improving the Capacity Of Cll To Function As Effective Antigsupporting

confidence: 67%

Cellular immune therapy for chronic lymphocytic leukemia

Kater

Oers

Kipps

2007

Blood

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“…It will be crucial to determine whether purified mutant p53 proteins with either codon 72 polymorphism can interact differently with purified p63/p73 proteins in vitro. As others have not observed a similar correlation, it is possible that multiple determinants such as cell type might modulate the influence of this polymorphism (Gaiddon et al, 2001;Willis et al, 2003).…”

Section: Introductionmentioning

confidence: 69%

“…It is therefore likely that a considerable surfeit of mutant p53 is needed for it to sequester the majority of p63 or p73. This may account for the observations of Willis et al (2003) who, using an elegant dual inducible promoter system to express both wild-type p73 and mutant p53 (R175H), failed to see an inhibitory effect of mutant p53 on p73b over a range of mutant p53/p73 ratios. Possibly they did not reach the same ratio of mutant p53 to p73 experimentally as found in some tumor cells.…”

Section: Mutant P53 and P63/p73: What Lies Ahead?mentioning

confidence: 98%

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

2007

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Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.

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“…Moreover, it has been reported that cellular stress signals can induce endogenous expression of p73 in p53 null or mutant cells, engaging a p53-independent apoptotic pathway [37,38]. Accordingly p73 seems to act as a cellular gatekeeper by preventing the proliferation of TQ-exposed Jurkat cells;…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

Alhosin

Abusnina

Achour

et al. 2010

Biochemical Pharmacology

132

116

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The salvage anti-tumoral pathway which implicates the p53-related p73 gene is not yet fully characterized. We therefore attempted to identify the up-and down-stream events involved in the activation of the p73-dependent pro-apoptotic pathway, by focusing on the anti-apoptotic and epigenetic integrator UHRF1 which is essential for cell cycle progression. For this purpose, we analyzed the effects of a known anti-neoplastic drug, thymoquinone (TQ), on the p53-deficient acute lymphoblastic leukemia (ALL) Jurkat cell line. Our results showed that TQ inhibits the proliferation of Jurkat cells and induces G1 cell cycle arrest in a dose-dependent manner. Moreover, TQ treatment triggers programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (m). TQ-induced apoptosis, confirmed by the presence of hypodiploid G0/G1 cells, is associated with a rapid and sharp re-expression of p73 and dose-dependent changes of the levels of caspase-3 cleaved subunits. These modifications are accompanied by a dramatic down-regulation of UHRF1 and two of its main partners, namely DNMT1 and HDAC1, which are all involved in the epigenetic code regulation. Knockdown of p73 expression restores UHRF1 expression, reactivates cell cycle progression and inhibits TQ-induced apoptosis. Altogether our results showed that TQ mediates its growth inhibitory effects on ALL p53-mutated cells via the activation of a p73-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets UHRF1.

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p73 can suppress the proliferation of cells that express mutant p53

Cited by 26 publications

References 72 publications

Cellular immune therapy for chronic lymphocytic leukemia

Cellular immune therapy for chronic lymphocytic leukemia

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

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