The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis

Xiong, Shunbin; Pant, Vinod; Zhang, Yun; Aryal, Neeraj K.; You, M. James; Kusewitt, Donna F.; Lozano, Guillermina

doi:10.1002/path.4854

Cited by 27 publications

(27 citation statements)

References 48 publications

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“…Although not the case in the cSCC lines examined, MDM2 depletion in some contexts can increase mutant p53 expression [ 91 ]. In addition, MDM2 and MDMX have been reported to suppress at least some gain of function activities of mutant p53 [ 92 , 93 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

et al. 2018

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We show that suppression of the spliceosome has potential for the treatment of cutaneous squamous cell carcinoma (cSCC). The small-molecule inhibitors of the spliceosome at the most advanced stage of development target the splicing factor SF3B1/SF3b155. The majority of cSCC cell lines are more sensitive than normal skin cells to death induced by the SF3B1 inhibitor pladienolide B. Knockdown of SF3B1 and a range of other splicing factors with diverse roles in the spliceosome can also selectively kill cSCC cells. We demonstrate that endogenous c-MYC participates in conferring sensitivity to spliceosome inhibition. c-MYC expression is elevated in cSCC lines and its knockdown reduces alterations in mRNA splicing and attenuates cell death caused by interference with the spliceosome. In addition, this study provides further support for a key role of the p53 pathway in the response to spliceosome disruption. SF3B1 inhibition causes wild-type p53 upregulation associated with altered mRNA splicing and reduced protein expression of both principal p53 negative regulators MDMX/MDM4 and MDM2. We observed that wild-type p53 can promote pladienolide B-induced death in tumour cells. However, p53 is commonly inactivated by mutation in cSCCs and p53 participates in killing normal skin cells at high concentrations of pladienolide B. This may limit the therapeutic window of SF3B1 inhibitors for cSCC. We provide evidence that, while suppression of SF3B1 has promise for treating cSCCs with mutant p53, inhibitors which target the spliceosome through SF3B1-independent mechanisms could have greater cSCC selectivity as a consequence of reduced p53 upregulation in normal cells.

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Section: Discussionmentioning

confidence: 99%

Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

et al. 2018

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“…Although less studied, MDMX has also been shown to regulate cellular processes independently of p53. MDMX can enhance tumor progression in some cases by promoting cancer cell growth and genomic instability (Kadakia et al 2002;Carrillo et al 2015;Xiong et al 2017). Supporting the idea that MDM2 and MDMX have p53-independent functions are data from human patients' tumors that do not harbor wild-type p53, but that do have amplified levels of MDM2 or MDMX or both.…”

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confidence: 92%

MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

et al. 2020

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MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q 10 , an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

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“…Upregulation of MDM4 has been identified in leukemia [35]. The p53 inhibitor MDM4 has been reported to be involved in tumorigenesis [36].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-532 inhibits cell growth and metastasis in retinoblastoma by targeting MDM4

Niu

Wang

et al. 2020

Preprint

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Background Now, numerous microRNAs (miRNAs) are found to exert effect in retinoblastoma (RB). This research mainly focused on the function of miR-532 in RB, which has not been investigated. Methods RT-qPCR and Western blot analysis were used to measure expressions of miR-532 and genes. Transwell, CCK-8 and luciferase reporter assays were applied to explore functions of miR-532 and MDM4 in RB. Results The expression of miR-532 was reduced in RB. Furthermore, overexpression of miR-532 restrained RB cell survival and metastasis and induced apoptosis. In addition, miR-532 directly targets MDM4. Moreover, downregulation of MDM4 blocked the progression of RB. And upregulation of MDM4 reversed the anti-tumor effect of miR-532 in RB. Conclusion MiR-532 inhibited cell viability and metastasis in RB by targeting MDM4, indicating that miR-532 may be a novel therapeutic target for RB patients.

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The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis

Cited by 27 publications

References 48 publications

Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

MicroRNA-532 inhibits cell growth and metastasis in retinoblastoma by targeting MDM4

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