A role for caspase 2 and PIDD in the process of p53-mediated apoptosis

Baptiste-Okoh, Nicole; Barsotti, Anthony M.; Prives, Carol

doi:10.1073/pnas.0711800105

Cited by 73 publications

(64 citation statements)

References 41 publications

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“…This is likely due to compromised transcriptional activity for p53(Gln-22/ Ser-23), which has a limited activity in regulating a subset of p53 target genes (18,30,31). As a result, thymus-specific knock-in of mouse p53(Gln-25/Ser-26) makes mice prone to thymus lymphomas, suggesting that transcriptional activity conferred by activation domain 1 is required for p53-dependent tumor suppression (32).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Functional Domains Necessary for Mutant p53 Gain of Function

Yan

Chen

2010

Journal of Biological Chemistry

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Tumor cells, including SW480 carcinoma cells that carry a mutant p53, are addicted to the mutant for their survival and resistance to growth suppression by chemotherapeutic agents. Here, we investigated whether various classes of p53 mutants share a common property and functional domains necessary for mutant p53 gain of function. To test this, we generated SW480 cell lines in which endogenous mutant R273H/P309S can be inducibly or stably knocked down, whereas a small interfering RNA-resistant mutant p53 along with a mutated functional domain can be inducibly or stably expressed. We found that both contact-site (R248W and R273H) and conformation (G245S and R249S) mutants are able to maintain the transformed phenotypes of SW480 cells conferred by endogenous mutant p53. We also found that activation domains 1-2 and the proline-rich domain are required for mutant p53 gain of function. Interestingly, we showed that the C-terminal basic domain, which is required for wild-type p53 activity, is an inhibitory domain for mutant p53. Furthermore, we showed that deletion of the basic domain enhances, whereas a mutation in activation domains 1-2 and deletion of the proline-rich domain abolish mutant p53 to regulate Gro1 and Id2, both of which are regulated by and mediate endogenous mutant p53 gain of function. These results indicate that both conformation and contact-site mutants share a property for cell transformation, and the domains critical for wild-type p53 tumor suppression are also required for mutant p53 tumor promotion. Thus, the inhibitory basic domain and the common property for p53 mutants can be explored for targeting tumors with mutant p53.

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Section: Discussionmentioning

confidence: 99%

Characterization of Functional Domains Necessary for Mutant p53 Gain of Function

Yan

Chen

2010

Journal of Biological Chemistry

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“…Recently, work conducted in H1299 cells showed that p53 QS was able to promote expression of some pro-apoptotic target genes such as PIDD and AIP1 and was able to induce apoptosis, although at a slower rate than wild type p53 (64). The study also reported that, even though many downstream apoptotic effectors are not induced by p53 QS , caspase-2 activation occurs, leading to cytochrome c release (64). Although MSL2 was shown to induce cytoplasmic localization of p53 QS , future studies may also focus on the regulation of some of these p53 target genes and the resulting activation of caspase-2 by MSL2.…”

Section: Discussionmentioning

confidence: 99%

MSL2 Promotes Mdm2-independent Cytoplasmic Localization of p53

Kruse

2009

Journal of Biological Chemistry

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Although it was originally thought of as a passive way to block the nuclear function of p53, accumulating evidence suggests that cytoplasmic localization of p53 plays an active role in p53-mediated functions such as apoptosis and autophagy. Previous studies by us and others demonstrated that Mdm2-mediated p53 ubiquitination induces both degradation and cytoplasmic localization. Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization.The function of the tumor suppressor p53 as a sequencespecific transcription factor controlling the expression of numerous target genes is critical for the regulation of cellular senescence, cell-cycle arrest, and apoptosis (1-3). During normal homeostasis, p53 is localized predominantly in the nucleus and is maintained at low levels via ubiquitination-mediated targeting for proteasomal degradation (4). Both protein levels and transcriptional activity increase dramatically in response to stress through an array of critical post-translational modifications (4, 5). Polyubiquitination of C-terminal lysines of p53 by Mdm2 (6 -8) and other ubiquitin-protein isopeptide ligases (E3) 2 such as Pirh2 (9), COP-1 (10), and Arf-BP1 (11) controls p53 levels by targeting p53 for proteasomal degradation in unstressed cells or after the cellular stress is resolved (4, 12). The stress-induced p53-dependent apoptotic response consists of transcription-dependent and -independent functions of p53 (13-17). Although transactivation of pro-apoptotic target genes such as PUMA, BAX, and PIG3 requires p53 to act as a transcription factor in the nucleus, cytoplasmic p53 can elicit an apoptotic response by localizing to the mitochondria and activating a direct mitochondrial death program (13, 18 -26). Mdm2-mediated p53 monoubiquitination, occurring when Mdm2 activity levels are low, promotes p53 nuclear export and the generation of a cytoplasmic p53 pools (27-32). Once p53 localizes to the mitochondria, both directly activated and enabled pathways are utilized to induce apoptosis (18). p53 interacts with anti-apoptotic members of the Bcl family such as BclXl and Bcl2 at the outer mitochondrial membrane to release and allow the oligomerization of the pro-apoptotic factors Bak and Bax. These in turn promote the formation of pores in the mitochondrial membrane resulting in the release of cytochrome c and other apoptotic activators from the mitochondria (21,22,(33)(34)(35). Alternatively, p53 can interact directly with Bak, releasing Bak from its inhibitory interaction with Mcl1 and thereby directly activating Bak-induced apoptosis (23, 36). Recently, a role for cytoplasmic p53 in autophagy was described, providing further evidence that changes on subcellular localization of p53 have pro...

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“…A p53 protein mutated at L22/W23 within TAD-I is largely inert, but surprisingly can still transactivate select proapoptotic genes (Johnson et al 2005;Baptiste-Okoh et al 2008), indicating that other regions such TAD-II and/or the proline-rich domain can independently function in transcriptional activation. On the other hand, a specific double mutation within TAD-II at W53/F54 selectively alters the transactivation of certain proapoptotic targets in yeast (Candau et al 1997) and human cells (Zhu et al 2000).…”

Section: Transcriptional Regulation By P53mentioning

confidence: 99%