PUMA Couples the Nuclear and Cytoplasmic Proapoptotic Function of p53

Abstract

The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that a tripartite nexus between Bcl-xL, cytoplasmic p53, and PUMA coordinates these distinct p53 functions. After genotoxic stress, Bcl-xL sequestered cytoplasmic p53. Nuclear p53 caused expression of PUMA, which then displaced p53 from Bcl-xL, allowing p53 to induce mitochondrial permeabilization. Mutant Bcl-xL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53.

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

“…PUMA was superior to p53, caspase 6, and caspase 8 with regard to the ability to induce cell death. On the other hand, results of a recent study suggested that p53 is intimately involved in PUMA-induced apoptosis through their mutual interactions with Bcl-x L (17). Hence, it is important to assess the relationship between p53 and PUMA for individual tissues and their respective unique cell types to understand the regulation of apoptosis and utility of targeting p53 versus more distal proteins such as PUMA as a therapeutic strategy.…”

Clues from worms: a Slug at Puma promotes the survival of blood progenitors

“…5,6 This intriguing finding placed Puma as the major apoptotic factor in the apoptotic pathway of p53 acting at the mitochondria. More recently, Chipuk et al 7 refined the contribution of Puma to the apoptotic activity p53 by showing that Puma relieves cytoplasmic p53 from the antiapoptotic Bcl-xL, allowing p53 to activate the proapoptotic Bax and induce mitochondrial outer membrane permeabilization and hence apoptosis. Thus, puma is the major target of p53 transcriptional-dependent apoptosis in thymocytes, and in turn contributes to the transcriptionalindependent apoptotic action of p53 at the mitochondria (Figure 1).…”

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

“…Interestingly, even when the above functions do not require p53-dependent transcription, activation of p53 target genes seems to influence the outcome of the cytoplasmic p53 response. The product of the p53-induced gene PUMA (p53-upregulated modulator of apoptosis), has been reported to cooperate with cytoplasmic p53 in the induction of apoptosis (Chipuk et al, 2005).In contrast, p53 induces the expression of DRAM (damage-regulated autophagy modulator) and sestrin 2, which facilitate the induction of autophagy (Crighton et al, 2006;Budanov and Karin, 2008;Maiuri et al, 2009). Therefore, cytoplasmic p53, through coordination with nuclear p53 functions, contributes in the execution of the p53 response.…”