USP49 participates in the DNA damage response by forming a positive feedback loop with p53

Tu, Rongfu; Kang, Wenqian; Yang, Xuechao; Zhang, Qi; Xie, Xiaoyu; Liu, Wenbin; Zhang, Jinxiang; Zhang, Xiaodong; Wang, Hui; Du, Ran

doi:10.1038/s41419-018-0475-3

Cited by 34 publications

(31 citation statements)

References 47 publications

(44 reference statements)

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“…Thus, USP49 could be as a novel tumor suppressor in tumors, at least in NSCLC and pancreatic cancer. USP49 was also reported participating in the DNA damage response by forming a positive feedback loop with p53 . In detail, USP49 interacted with the N terminus of p53 and inhibited several types of p53 ubiquitination, as a result of which, USP49 had a positive effect on p53 transcriptional activity and protein stability, which further indicated that USP49 could display potential anti‐tumor activity on tumors .…”

Section: Discussionmentioning

confidence: 93%

“…USP49 was also reported participating in the DNA damage response by forming a positive feedback loop with p53 . In detail, USP49 interacted with the N terminus of p53 and inhibited several types of p53 ubiquitination, as a result of which, USP49 had a positive effect on p53 transcriptional activity and protein stability, which further indicated that USP49 could display potential anti‐tumor activity on tumors . Additionally, USP49 rendered colorectal cancer cells more sensitive to etoposide‐induced DNA damage, and was increased in response to DNA damage, which indicated that the expression of USP49 might affect the effect of radiotherapy and chemotherapy in NSCLC that will be verificated in the future …”

Section: Discussionmentioning

confidence: 95%

“…27 Additionally, USP49 rendered colorectal cancer cells more sensitive to etoposide-induced DNA damage, and was increased in response to DNA damage, which indicated that the expression of USP49 might affect the effect of radiotherapy and chemotherapy in NSCLC that will be verificated in the future. 27…”

Section: Usp49 Deubiquitinates and Stabilizes Pten In Nsclc Cellsmentioning

confidence: 99%

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Ubiquitin specific peptidase 49 inhibits non‐small cell lung cancer cell growth by suppressing PI3K/AKT signaling

Shen

Yin

et al. 2019

The Kaohsiung J of Med Scie

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Ubiquitin specific peptidase 49 (USP49) has been reported as a tumor suppressor in several tumors, but its function and molecular mechanism in non‐small cell lung cancer (NSCLC) are still unknown. In this study, USP49 was found downregulated in NSCLC primary tissues and cell lines, and high USP49 predicted a positive index for the overall survival of NSCLC patients. Overexpression of USP49 downregulated the expression levels of Cyclin D1, and upregulated p53 expression. Further flow cytometry analysis showed that overexpressed USP49 induced cell cycle arrest at G0/G1 phase. As a result, overexpression of USP49 significantly inhibited cell growth of NSCLC cells. In mechanism, overexpression of USP49 inhibited PI3K/AKT signaling, but knockdown of USP49 enhanced this signaling. Further studies indicated that USP49 deubiquitinated PTEN and stabilized PTEN protein, which suggested that USP49 inhibited PI3K/AKT signaling by stabilizing PTEN in NSCLC cells. In conclusion, we demonstrated that USP49 was functional in NSCLC cells, and inhibited NSCLC cell growth by suppressing PI3K/AKT signaling, suggesting that USP49 could be as a novel target for NSCLC therapy.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 95%

Section: Usp49 Deubiquitinates and Stabilizes Pten In Nsclc Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Ubiquitin specific peptidase 49 inhibits non‐small cell lung cancer cell growth by suppressing PI3K/AKT signaling

Shen

Yin

et al. 2019

The Kaohsiung J of Med Scie

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“…In current study, we considered the effect of MDM2-p53 mRNA binding to enhance p53 mRNA translation [15]. Notably, the p53 system is pervaded with positive feedback loops [8][9][10]. Incorporating any positive feedback loop in our model may support the p53 terminal pulses although the detailed mechanisms and kinetic parameters may differ (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…ataxia-telangiectasia-mutated, ATM) [7]. There are a number of positive and negative auto-regulatory feedback loops which actively participate in the regulation of p53 network [8][9][10]. Consequently, the p53 dynamics at single cell levels under DNA damage exhibit complex patterns ranging from spontaneous or synchronized pulses to sustained elevation [4,[11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Mathematical model identifies effective P53 accumulation with target gene binding affinity in DNA damage response for cell fate decision

Sun

Cui

2018

Cell Cycle

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Functional p53 signaling is essential for appropriate responses to diverse stimuli. P53 dynamics employs the information from the stimulus leading to selective gene expression and cell fate decision. However, the decoding mechanism of p53 dynamics under DNA damage challenge remains poorly understood. Here we mathematically modeled the recently dual-phase p53 dynamics under doxorubicin treatment. We found that p53 could perform sequential pulses followed by a high-amplitude terminal pulse at relatively low doxorubicin treatment, whereas p53 became steadily accumulated when damage level was high. The effective p53 integral above a threshold but not the absolute accumulation of p53 precisely discriminated survival and death. Silencing negative regulators in p53 network might promote the occurrence of terminal pulse. Furthermore, lower binding affinity and degradation rate of p53 target genes could favorably discriminate high and low dose doxorubicin treatment. Grouping by temporal profiles suggested that the p53 dynamics rather than the doxorubicin doses could better discriminate cellular outcomes and confer less variation for effective p53 integral reemphasizing the importance of p53 level regulation. Our model has established a theoretical framework that p53 dynamics can work cooperatively with its binding affinity to target genes leading to cell fate choice, providing new clues of optimized clinical design by manipulating p53 dynamics. ARTICLE HISTORY

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Deubiquitylating Enzymes in Cancer and Immunity

Ren,

Yu,

Liu

et al. 2023

Advanced Science

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Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post‐translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein–protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs’ functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus‐faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi‐faced roles of DUBs in cancer and immunity.

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USP49 participates in the DNA damage response by forming a positive feedback loop with p53

Cited by 34 publications

References 47 publications

Ubiquitin specific peptidase 49 inhibits non‐small cell lung cancer cell growth by suppressing PI3K/AKT signaling

Ubiquitin specific peptidase 49 inhibits non‐small cell lung cancer cell growth by suppressing PI3K/AKT signaling

Mathematical model identifies effective P53 accumulation with target gene binding affinity in DNA damage response for cell fate decision

Deubiquitylating Enzymes in Cancer and Immunity

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