p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

Abstract

The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Conversely, p53 function is altered or attenuated in one way or another in the majority of human cancers. Besides its well-understood action as a transcriptional regulator of multiple apoptotic genes, p53 also exerts a direct pro-apoptotic role at the mitochondria by engaging in protein-protein interactions with anti-and pro-apoptotic Bcl2 family members, thereby executing the shortest known circuitry of p53 death signaling. Nur77, also known as TR3 or NGFI-B, is a unique transcription factor belonging to the orphan nuclear receptor superfamily. Even more extreme than p53, Nur77 can exert opposing biological activities of survival and death. Its activities are regulated by subcellular distribution, expression levels, protein modification and heterodimerization with retinoid X receptor. In cancer cells, Nur77 functions in the nucleus as an oncogenic survival factor, but becomes a potent killer when certain death stimuli induce its migration to mitochondria, where it binds to Bcl2 and conformationally converts it to a killer that triggers cytochrome c release and apoptosis. This review focuses on their unexpected transcription-independent pro-death programs at mitochondria and highlights the remarkable mechanistic similarities between them. Moreover, an accumulating body of evidence provides ample rationale to further investigate how these mitochondrial p53 and Nur77 pathways could become exploitable targets for new cancer therapeutics.

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

“…Nur77, another NR4A family member, has been reported to exert opposing biologic activities of cell survival and death depending on the modulation of its presenting status. 23 We have previously reported on a novel ligand that can activate Nurr1 in bladder cancer cells, resulting in the release of tumor necrosis factor-related apoptosis inducing ligand and apoptosis. 24 Uniquely, nuclear to cytoplasmic shuttling of Nur77 has been suggested to be a molecular switch that dislodges the Bcl-2 BH4 domain, exposing its BH3 domain, which in turn blocks the activity of antiapoptotic Bcl-X(L).…”

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

“…Cellular stress signals such as DNA damage interrupt Mdm2-mediated inhibition of p53, leading to accumulation of p53 both in the nucleus and in the cytoplasm. Multiple mechanisms have been invoked to explain how p53 triggers ''mitochondrial outer membrane permeabilization'' (Moll et al 2006). In apoptotic cells, p53 coimmunoprecipitates with Bcl2, Bcl-XL and Bak (Leu et al 2004;Moll et al 2006).…”

“…Multiple mechanisms have been invoked to explain how p53 triggers ''mitochondrial outer membrane permeabilization'' (Moll et al 2006). In apoptotic cells, p53 coimmunoprecipitates with Bcl2, Bcl-XL and Bak (Leu et al 2004;Moll et al 2006). According to Mihara et al (2003), p53 binds to Bcl-XL via its DNA binding domain.…”

Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma

“…In contrast, wild-type p53 expressing colon carcinoma cells (RKO), with lower levels of p53 ubiquitylation than NB cells (Figure 1 In addition to p53's transcriptional role, stress-induced p53 translocation to mitochondria which induces outer mitochondrial membrane permeabilization is a common early component in p53-mediated apoptosis in normal and transformed cells. 29 Importantly, in contrast to non-NB cells that contain functional wtp53 such as RKO and ML1, both NB lines tested (CHP134 and LAN5) are markedly impaired in their ability to undergo stress-induced mitochondrial translocation (Figure 2b). This further supports the notion that cytoplasmically accumulated p53 in NB is inactive in mediating apoptosis.…”