DNA damage-induced activation of ATM promotes β-TRCP-mediated Mdm2 ubiquitination and destruction

DNA damage-induced activation of ATM promotes β-TRCP-mediated Mdm2 ubiquitination and destruction

ABSTRACT

The Mdm2 oncoprotein promotes p53 ubiquitination and destruction. Yet, exact molecular mechanisms of Mdm2 destruction itself, under DNA damaging conditions, remain unclear. Recently, we identified SCFβ-TRCP as a novel E3 ligase that targets Mdm2 for ubiquitination and destruction in a Casein Kinase Iδ (CKIδ)-dependent manner. However, it remains elusive how the β-TRCP/CKIδ/Mdm2 signaling axis is regulated by DNA damage signals to govern p53 activity. Consistent with previous studies, we found that inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase, in turn, impaired DNA damage-induced Mdm2 destruction. Although phosphorylation of Mdm2 at Ser395 (an ATM phosphorylation site) facilitated Mdm2 interaction with β-TRCP, Ser395A-Mdm2 was degraded non-distinguishably from WT-Mdm2 by SCFβ-TRCP upon DNA damaging treatments. This indicates that in addition to phosphorylating Mdm2 at Ser395, ATM may govern Mdm2 stability through other unknown mechanisms. We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKIδ at two well-conserved S/TQ sites, which promotes CKIδ nuclear localization to increase CKIδ-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCFβ-TRCP. Our studies provide a molecular mechanism of how ATM could govern DNA damage-induced destruction of Mdm2 in part by phosphorylating both Mdm2 and CKIδ to modulate SCFβ-TRCP–mediated Mdm2 ubiquitination. Given the pivotal role of Mdm2 in the negative regulation of p53, this work will also provide a rationale for developing CKIδ or ATM agonists as anti-cancer agents.



When general population speak of modern medicine, accuracy plays one of the most significant roles and human lives are directly dependent on it. Hereby, any researches pertaining to medicine are required to comply with the top standards. The issue nowadays is that any results of researches can be shared online and used as a reference without being properly checked and approved. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this issue and decided to develop an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been established back in 2010. The major principle of this journal is related to Altmetric scores that are used as a quality measure. That assists both readers and authors to quality-check publications with Altmetric Article Reports that generate “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a complete publications list with respective scores higher than 100 as well as reports mentioned above. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it creates the necessary help to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was published back in 2018 by Oncotarget and written by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are willing to understand the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Likewise, the article about melanoma, was utilized for citations in various news articles 69 times. Moreover, it was quoted in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is proud to have the ability to share with online viewers this highly appreciated and top-quality information, that is trustworthy and reliable.
https://en.wiktionary.org/wiki/oncotarget

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