TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity

Tomasini, Richard; Tsuchihara, Katsuya; Tsuda, Chiharu; Lau, Susan; Wilhelm, Margareta; Ruffini, Alessandro; Tsao, Ming‐Sound; Iovanna, Juan; Jurisicova, Andrea; Melino, Gerry; Mak, Tak W.

doi:10.1073/pnas.0812096106

Cited by 116 publications

(116 citation statements)

References 50 publications

(60 reference statements)

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“…siRNA used for TAp73 downregulation were done as previously mentioned. 20 TGF-β1 treatment. Cells were incubated for 12 or 24 h with various concentrations (0, 1 or 5.0 ng/ml) of mouse TGF-β1 (mTGF-β1; Cell Signaling Technology, Beverly, MA, USA) before being continually cultured for different time periods in growth medium.…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that loss of the full p73 isoform TAp73 (transcriptionally active p73), containing the transactivation domain similar to p53, induced spontaneous tumor development because of enhanced genomic instability. 19,20 Interestingly, such genomic instability with loss of the spindle assembly checkpoint, was also reported in PDA where it was found associated with p73 inhibition. 21 Moreover, although mutations in TP73 are less frequent in human cancers than those of TP53, genetic aberrations of TP73 were reported in pancreatic cancer and correlated with patient outcome.…”

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confidence: 92%

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TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

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Section: Methodsmentioning

confidence: 99%

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confidence: 92%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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“…These include, but are not limited to, the activation of the DNA damage-responsive protease caspase-2, 114 of the tumor suppressor TP53 109,115 and of other members of the TP53 family, including the TP73 variant TAp73. 116,117 In view of recent results from several laboratories indicating that mitotic aberrations can induce cell senescence, [118][119][120] and that cell death can be either apoptotic or necrotic, 8 we have recently proposed a novel definition and categorization of mitotic catastrophe based on purely functional considerations. 108 Thus, mitotic catastrophe would not constitute a 'pure' cell death executioner pathway, but an oncosuppressive mechanism that: (i) is initiated by perturbations of the mitotic apparatus (i.e., chromosomes and the complex Figure 3 Regulated necrosis.…”

Section: Definition Of 'Mitotic Catastrophe'mentioning

confidence: 99%

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

et al. 2011

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proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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“…[1][2][3] Whereas p53 is a tumor suppressor and often either deleted or mutated in tumors, p73 is rarely mutated; however, its expression is often deregulated in cancer. 4,5 In p73-deficient mice, unlike in p53-deficient mice, no increase in spontaneous tumorigenesis is observed. 6 It has been demonstrated, however, that p73, in the absence of DNA damage, has a role in neuronal differentiation and development.…”

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confidence: 99%

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

Agostini

et al. 2013

Cell Death Differ

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p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in regulating lipid metabolism by direct transactivation of the promoter of autophagy-related protein 5 (ATG5), a gene whose product is required for autophagosome formation. Following nutrient deprivation, the livers of p73-deficient mice demonstrate a massive accumulation of lipid droplets, together with a low level of autophagy, suggesting that triglyceride hydrolysis into fatty acids is blocked owing to deficient autophagy (macrolipophagy). Compared with wild-type mice, mice functionally deficient in all the p73 isoforms exhibit decreased ATG5 expression and lower levels of autophagy in multiple organs. We further show that the TAp73a is the critical p73 isoform responsible for inducing ATG5 expression in a p53-independent manner and demonstrate that ATG5 gene transfer can correct autophagy and macrolipophagy defects in p73-deficient hepatocytes. These data strongly suggest that the p73-ATG5 axis represents a novel, key pathway for regulating lipid metabolism through autophagy. The identification of p73 as a major regulator of autophagy suggests that it may have an important role in preventing or delaying disease and aging by maintaining a homeostatic control. Cell Death and Differentiation (2013) 20, 1415-1424; doi:10.1038/cdd.2013.104; published online 2 August 2013 p73 belongs to the p53 family, a group of transcription factors that have key roles in the regulation of many cellular processes, such as apoptosis, cell cycle, and senescence, especially following DNA damage. 1-3 Whereas p53 is a tumor suppressor and often either deleted or mutated in tumors, p73 is rarely mutated; however, its expression is often deregulated in cancer. 4,5 In p73-deficient mice, unlike in p53-deficient mice, no increase in spontaneous tumorigenesis is observed. 6 It has been demonstrated, however, that p73, in the absence of DNA damage, has a role in neuronal differentiation and development. 6-9 Consequently, p73-deficient mice exhibit neurological defects and, even though no obvious deficiencies in lymphoid or granulocyte populations have been so far detected, such mice show deregulated inflammatory responses and senescence. 6,10 Because of splicing events occurring near the 3 0 end of the coding region and because of an alternative promoter located in the third intron of the gene, p73 exists as multiple protein variants. 11 The isoforms containing a transactivation (TA) domain (TAp73s) generally behave like p53 with respect to overlapping promoters and biological functions. 2,4 For instance, in contrast to p73-deficient mice, TAp73 knockout mice showed spontaneous as well as carcinogen-induced tumors, indicating that TAp73 is a tumor suppressor. 12 The alternative promoter also produces amino-terminal truncated DN isoforms, the so-called ...

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TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity

Cited by 116 publications

References 50 publications

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

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