Guardian of genome on the tract: Wild type p53-mdm2 complex inhibition in healing the breast cancer

Janani, S.; Dhanabal, S P; Sureshkumar, R.; Surya, Nikitha Upadhyayula Sai; Karthika, Chenmala

doi:10.1016/j.gene.2021.145616

Cited by 3 publications

(6 citation statements)

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“…In addition to defective p53 pathway due to somatic mutations, p53 activities may be downregulated by other mechanisms. The level of p53 protein in the cell is dependent on the rate of ubiquitination‐dependent protein degradation 8 . Mouse double minute 2 homolog (MDM2) is an E3 ubiquitin‐protein ligase that has p53 protein as its substrate.…”

Section: Introductionmentioning

confidence: 99%

“…MDM2 is overexpressed in a number of cancers, including breast cancer and HCC 10 . High levels of MDM2 were observed in advanced‐stage breast cancer and squamous cell carcinomas with wild‐type p53, indicating inhibition of p53 activities by MDM2 is a cause of cancer 8,11 . The p53 binding site of MDM2 overlaps with the transactivation domain in p53, which is an additional mechanism of p53 inhibition by MDM2.…”

Section: Introductionmentioning

confidence: 99%

“…The level of p53 protein in the cell is dependent on the rate of ubiquitination-dependent protein degradation. 8 Mouse double minute 2 homolog (MDM2) is an E3 ubiquitin-protein ligase that has p53 protein as its substrate. MDM2 is a multi-domain protein that contains the p53-binding domain, acidic domain, zinc finger, and RING domain.…”

mentioning

confidence: 99%

“…10 High levels of MDM2 were observed in advanced-stage breast cancer and squamous cell carcinomas with wild-type p53, indicating inhibition of p53 activities by MDM2 is a cause of cancer. 8,11 The p53 binding site of MDM2 overlaps with the transactivation domain in p53, which is an additional mechanism of p53 inhibition by MDM2. The design of therapeutic agents to block the interactions between p53 and MDM2 has been an active area to develop anticancer drugs.…”

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confidence: 99%

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Retracted: Structural studies of antitumor compounds that target the RING domain of MDM2

et al. 2022

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Mouse double minute 2 homolog (MDM2) is an E3 ubiquitin‐protein ligase that is involved in the transfer of ubiquitin to p53 and other protein substrates. The expression of MDM2 is elevated in cancer cells and inhibitors of MDM2 showed potent anticancer activities. Many inhibitors target the p53 binding domain of MDM2. However, inhibitors such as Inulanolide A and MA242 are found to bind the RING domain of MDM2 to block ubiquitin transfer. In this report, crystal structures of MDM2 RING domain in complex with Inulanolide A and MA242 were solved. These inhibitors primarily bind in a hydrophobic site centered at the sidechain of Tyr489 at the C‐terminus of MDM2 RING domain. The C‐terminus of MDM2 RING domain, especially residue Tyr489, is required for ubiquitin discharge induced by MDM2. The binding of these inhibitors at Tyr489 may interrupt interactions between the MDM2 RING domain and the E2‐Ubiquitin complex to inhibit ubiquitin transfer, regardless of what the substrate is. Our results suggest a new mechanism of inhibition of MDM2 E3 activity for a broad spectrum of substrates.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Retracted: Structural studies of antitumor compounds that target the RING domain of MDM2

et al. 2022

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“…TP53 mutations may have varied effects depending on the breast tumor subtypes. There is now evidence that inactivation of p53 by mutation, amplification of MDM2 or MDM4, or infrequent alterations in other p53 pathway components causes luminal cancers [26].…”

Section: P53 -A Guardian Of the Genome And Beyondmentioning

confidence: 99%

Role of p53 in Human Cancers

Coşkun¹,

Tutar²,

Al³

et al. 2022

P53 - A Guardian of the Genome and Beyond

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TP53 codes tumor protein 53-p53 that controls the cell cycle through binding DNA directly and induces reversible cell-cycle arrest. The protein activates DNA repair genes if mutated DNA will be repaired or activates apoptotosis if the damaged DNA cannot be fixed. Therefore, p53, so-called the “guardian of the genome,” promote cell survival by allowing for DNA repair. However, the tumor-suppressor function of p53 is either lost or gained through mutations in half of the human cancers. In this work, functional perturbation of the p53 mechanism is elaborated at the breast, bladder, liver, brain, lung cancers, and osteosarcoma. Mutation of wild-type p53 not only diminishes tumor suppressor activity but transforms it into an oncogenic structure. Further, malfunction of the TP53 leads accumulation of additional oncogenic mutations in the cell genome. Thus, disruption of TP53 dependent survival pathways promotes cancer progression. This oncogenic TP53 promotes cell survival, prevents cell death through apoptosis, and contributes to the proliferation and metastasis of tumor cells. The purpose of this chapter is to discuss the contribution of mutant p53 to distinct cancer types.

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Small molecules targeting protein–protein interactions for cancer therapy

Yang

Zheng

et al. 2023

Acta Pharmaceutica Sinica B

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Guardian of genome on the tract: Wild type p53-mdm2 complex inhibition in healing the breast cancer

Cited by 3 publications

References 50 publications

Retracted: Structural studies of antitumor compounds that target the RING domain of MDM2

Retracted: Structural studies of antitumor compounds that target the RING domain of MDM2

Role of p53 in Human Cancers

Small molecules targeting protein–protein interactions for cancer therapy

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