The p53–Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity

Pant, Vinod; Xiong, Shunbin; Jackson, James G.; Post, Sean M.; Abbas, Hussein A.; Quintás‐Cardama, Alfonso; Hamir, A. N.; Lozano, Guillermina

doi:10.1101/gad.227249.113

Cited by 69 publications

(97 citation statements)

References 46 publications

(72 reference statements)

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“…Using the mouse model in which the p53-Mdm2 feedback loop is disrupted, we observed that DNA damage-stabilized p53 degraded just like in wild-type tissues, but the rate of degradation was slightly delayed. This suggests that other proteins cooperate with Mdm2 in degradation of p53 after stress (Pant et al 2013;Pant and Lozano 2014). Unfortunately, ubiquitination was not assayed in tissues from these mice due to technical challenges.…”

Section: Mdm2 Is Not Alonementioning

confidence: 99%

“…We recently tested this paradigm in a mouse model in which the feedback loop was disrupted due to mutations in the p53-binding sites in the Mdm2 P2 promoter. While mice lacking the p53-binding sequences in the P2 promoter are normal, they exhibit hematopoietic defects and die after exposure to low-dose ionizing radiation (Pant et al 2013;Pant and Lozano 2014).…”

Section: The Mdm2 E3 Ligasementioning

confidence: 99%

“…In fact, Mdm2 is such a potent inhibitor that it probably masks functions of other E3 ligases that might fine-tune p53 activities in vivo. To overcome this, in vivo models in which Mdm2 levels are low, as in hypomorphic Mdm2 (Mendrysa et al 2003), or in which they cannot be induced further, such as in Mdm2 P2/P2 mice (Pant et al 2013), could be used. A combinatorial analysis of other ligases might provide insights as to their importance.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Limiting the power of p53 through the ubiquitin proteasome pathway

2014

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The ubiquitin proteasome pathway is critical in restraining the activities of the p53 tumor suppressor. Numerous E3 and E4 ligases regulate p53 levels. Additionally, deubquitinating enzymes that modify p53 directly or indirectly also impact p53 function. When alterations of these proteins result in increased p53 activity, cells arrest in the cell cycle, senesce, or apoptose. On the other hand, alterations that result in decreased p53 levels yield tumor-prone phenotypes. This review focuses on the physiological relevance of these important regulators of p53 and their therapeutic implications.

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Section: Mdm2 Is Not Alonementioning

confidence: 99%

Section: The Mdm2 E3 Ligasementioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

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Limiting the power of p53 through the ubiquitin proteasome pathway

2014

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“…Under normal physiological conditions, the anti-proliferative functions of p53 are strictly inhibited, mainly by the actions of an E3 ubiquitin ligase, MDM2, which mediates p53 ubiquitination and degradation. The MDM2 gene is also a p53 target, which forms a feedback loop that restrains p53 activity (Pant et al 2013). The negative regulation of p53 by MDM2 has been genetically confirmed, as the early embryonic lethality caused by deletion of the MDM2 gene can be rescued by p53 deletion (Montes de Oca Luna et al 1995).…”

mentioning

confidence: 93%

Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation

et al. 2015

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The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2-RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2-RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11-MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.

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“…In most of human cancers (Ozaki and Nakagawara, 2011), p53's functions are compromised either by loss-of-function mutations or by the defects that occur in the other components of the pathway. Under normal conditions, the p53 is strictly inhibited mainly by an E3 ubiquitin ligase, murine double minute 2 (MDM2), which inhibits p53 transcription activity and also mediates p53 ubiquitination and degradation (Pant et al, 2013). MDM2 is the best characterized negative regulator of p53.…”

mentioning

confidence: 99%

Complex Structures of Human MDM2 with Interacting Proteins Reveal the Regulation Mechanism of p53

Yang¹,

Dong²,

Wu³

et al. 2018

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Abstract. Human MDM2 (murine double minute 2), amplified and overexpressed frequently in most of tumors and cancers, directly interacts with and inhibits the tumor suppressor protein p53. Understanding the regulation mechanism of MDM2 has recently been highlighted because of its roles in the regulation of p53 in cancer biology. MDM2 contains three domains. The N-terminal region interacts with p53 and downregulates its activity. The RING finger domain has ubiquitin ligase activity that can mediate p53 ubiquitination and degradation. Many studies showed that the central region of MDM2 is critical for p53 activation and tumor suppression. To date, more than twenty proteins have been shown to bind to this central region and further to be involved in the regulations of p53. However, how these interacting proteins precisely interact with MDM2 remains to be elucidated. We solved the first structure of the human MDM2-RPL11 complex. Both the acidic domain and C4 zinc finger of MDM2 are essential for RPL11 binding. Moreover, another unexpectedly zinc finger that forms inter-molecularly within the complex. A small molecule imidazole was found to be chelated in this zinc finger, which might be a promising start of drug design. These structural and functional information combining with earlier studies of MDM2 with other interacting proteins establish MDM2 as a novel class of therapeutic targets in human diseases such as cancers, yield insights into the MDM2-p53 surveillance pathway and could also yield useful anticancer strategies.Inactivation of tumor suppressor genes and activation of oncogenes could lead to tumorigenesis. The well-studied tumor suppressor p53 is a transcription factor that can upregulate many downstream genes that are involved in cell cycle arrest and apoptosis (Vousden and Prives, 2009). p53 plays a critical role in tumor suppression and its inactivation has been linked to tumorigenesis. In most of human cancers (Ozaki and Nakagawara, 2011), p53's functions are compromised either by loss-of-function mutations or by the defects that occur in the other components of the pathway. Under normal conditions, the p53 is strictly inhibited mainly by an E3 ubiquitin ligase, murine double minute 2 (MDM2), which inhibits p53 transcription activity and also mediates p53 ubiquitination and degradation (Pant et al., 2013). MDM2 is the best characterized negative regulator of p53. MDM2 has gained much attention for its special functions in regulating p53. There are different factors controlling the MDM2-p53 signaling in response to different stresses, such as DNA damage, oncogenic activation, and ribosomal stress (Zhou et al., 2012). DNA damage mediated by ATM/ATR kinases, oncogenic stresses by ARF induction and ribosomal stress through ribosomal proteins represent three major p53-activating pathways. 203MDM2 encodes three domains: the N-terminal p53-binding region, the C-terminal RING finger domain, and the central region that includes an acidic region and a C4 zinc finger domain. The N-terminal region downregulates p5...

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The p53–Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity

Cited by 69 publications

References 46 publications

Limiting the power of p53 through the ubiquitin proteasome pathway

Limiting the power of p53 through the ubiquitin proteasome pathway

Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation

Complex Structures of Human MDM2 with Interacting Proteins Reveal the Regulation Mechanism of p53

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