TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma

Müller, Martina; Schilling, Tobias; Sayan, Emre; Kairat, Astrid; Lorenz, K.; Schulze‐Bergkamen, Henning; Oren, Moshe; Koch, Andreas; Tannapfel, Andrea; Stremmel, Wolfgang; Melino, Gerry; Krammer, Peter H.

doi:10.1038/sj.cdd.4401774

Cited by 174 publications

(165 citation statements)

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“…A good example of this is the ability of p53 and p73 to upregulate the expression of KILLER/ DR5 and several caspases (Takimoto and El-Deiry, 2000;MacLachlan and El-Deiry, 2002;Muller et al, 2005). So, if either TAp73 or p53 is present in a cell, that cell can be considered as already preconditioned for death receptor-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The TP53 gene is mutated and mutant p53 protein is accumulated in at least 50% of cancers (Sigal and Rotter, 2000). On the other hand, the TP73 gene is very rarely mutated and overexpression of TAp73 is often observed in tumors (Zaika et al, 1999;Stiewe and Putzer, 2000;Sayan et al, 2001;Muller et al, 2005). The new transcriptionindependent function of p73 and p53 (Sayan et al, 2006) suggests new approaches to chemotherapy, which do not require transcriptionally active p53 family members.…”

Section: Discussionmentioning

confidence: 99%

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p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

Sayan

Gogvadze

et al. 2008

Oncogene

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The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription-deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcriptionindependent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

Sayan

Gogvadze

et al. 2008

Oncogene

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“…The prevalent tumor suppressor function of p53 is also suggested by the observation that p53-inactivating mutations are very common in tumors whereas, in contrast, mutations in p63 and p73 are rarely observed in human malignancies (21)(22)(23). p63 and p73, however, may have a role in tumor progression as suggested by the observation that the dominant negative isoforms DNp63 and DNp73 are frequently up-regulated in cancer (24)(25)(26)(27)(28)(29)(30)(31)(32).…”

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confidence: 99%

TAp73α Increases p53 Tumor Suppressor Activity in Thyroid Cancer Cells via the Inhibition of Mdm2-Mediated Degradation

Malaguarnera

Vella

Pandini

et al. 2008

Molecular Cancer Research

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p53 family proteins include p53 tumor suppressor, p63, and p73. Despite the high similarity in structure and function with p53, p63, and p73 function in tumor suppression is still controversial. Here, we show that TAp73A, a transcriptionally active p73 isoform, is able to synergize p53 tumor suppressor function in thyroid cancer cells. Indeed, depletion of p73 by small interfering RNA in thyroid cancer cells resulted in a reduced transcriptional activity of p53.

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“…However, the transactivating full-length (TA) p73 rapidly accumulates in response to genotoxic stress. 69 Overexpression of TAp73 results in increased expression of genes encoding death receptors 70 and proapoptotic proteins, 71 thereby sensitizing cells to chemotherapeutic agents. 72,73 Importantly, TAp73 can mediate apoptosis independent of functional p53 74,75 and can sensitize p53-deficient tumors to chemotherapy.…”

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

confidence: 99%

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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TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma

Cited by 174 publications

References 38 publications

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

TAp73α Increases p53 Tumor Suppressor Activity in Thyroid Cancer Cells via the Inhibition of Mdm2-Mediated Degradation

Cellular immune therapy for chronic lymphocytic leukemia

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