Objective:Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment.We previously reported that high murine double minute 1(MDM1)expression ...Objective:Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment.We previously reported that high murine double minute 1(MDM1)expression in patients with rectal cancer is linked to a favorable chemoradiation response.In this study the role of MDM1 in the chemoradiotherapy response in colorectal cancer(CRC)patients was evaluated.Methods:Colony formation and cell proliferation assays as well as xenograft models were used to determine if MDM1 expression affects the sensitivity of CRC cells to chemoradiation.RNA sequencing revealed that MDM1 regulates tumor protein 53(TP53)expression and apoptosis.A series of molecular biology experiments were performed to determine how MDM1 affects p53 expression.The effects of inhibitors targeting apoptosis on MDM1 knockout cells were evaluated.Results:Gene expression profiling revealed that MDM1 is a potential chemoradiotherapy sensitivity marker.The sensitivity of CRC cells to chemoradiation treatment decreased after MDM1 knockout and increased after MDM1 overexpression.MDM1 affected p53 expression,thereby regulating apoptosis.MDM1 overexpression limited YBX1 binding to TP53 promoter,regulated TP53 expression,and rendered CRC cells more sensitive to chemoradiation.In CRC cells with low MDM1 expression,a combination of apoptosis-inducing inhibitors and chemoradiation treatment restored sensitivity to cancer therapy.Conclusions:The current study showed that MDM1 expression influences the sensitivity of CRC cells to chemoradiation by influencing p53 and apoptosis pathways,which is the basis for the underlying molecular mechanism,and serves as a possible predictive marker for chemoradiotherapy prognosis.展开更多
Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in man...Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
p53是重要的抑癌基因,在细胞周期阻滞、DNA损伤修复及细胞凋亡等生物过程中发挥重要作用,并已成为潜在的肿瘤治疗靶点。MDM2(Mdm2 p53 binding protein homolog)及MDMX(Mdm4 p53 binding protein homolog)是p53的主要抑制因子,两者相互...p53是重要的抑癌基因,在细胞周期阻滞、DNA损伤修复及细胞凋亡等生物过程中发挥重要作用,并已成为潜在的肿瘤治疗靶点。MDM2(Mdm2 p53 binding protein homolog)及MDMX(Mdm4 p53 binding protein homolog)是p53的主要抑制因子,两者相互协同并通过不同的信号途径抑制p53的活性。MDM2是p53的E3连接酶,介导p53的泛素化从而降低p53的稳定性。MD-MX则主要通过与p53的转录活性区结合,抑制p53对其下游基因的转录活性,但并不介导p53的降解。MDM2与MDMX通过不同机制协同对p53产生抑制作用,其具体分子过程及作用机制繁多且复杂。本文就p53。展开更多
Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address t...Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.展开更多
基金supported by grants from the National Natural Science Foundation(Grant No.81972859 to W.T.)Beijing Municipal Science&Technology Commission Grant(Grant No.D0905001040531 to D.L.)State Key Laboratory of Molecular Oncology Grant(Grant No.SKLMO-KF2023-03 to D.L.).
文摘Objective:Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment.We previously reported that high murine double minute 1(MDM1)expression in patients with rectal cancer is linked to a favorable chemoradiation response.In this study the role of MDM1 in the chemoradiotherapy response in colorectal cancer(CRC)patients was evaluated.Methods:Colony formation and cell proliferation assays as well as xenograft models were used to determine if MDM1 expression affects the sensitivity of CRC cells to chemoradiation.RNA sequencing revealed that MDM1 regulates tumor protein 53(TP53)expression and apoptosis.A series of molecular biology experiments were performed to determine how MDM1 affects p53 expression.The effects of inhibitors targeting apoptosis on MDM1 knockout cells were evaluated.Results:Gene expression profiling revealed that MDM1 is a potential chemoradiotherapy sensitivity marker.The sensitivity of CRC cells to chemoradiation treatment decreased after MDM1 knockout and increased after MDM1 overexpression.MDM1 affected p53 expression,thereby regulating apoptosis.MDM1 overexpression limited YBX1 binding to TP53 promoter,regulated TP53 expression,and rendered CRC cells more sensitive to chemoradiation.In CRC cells with low MDM1 expression,a combination of apoptosis-inducing inhibitors and chemoradiation treatment restored sensitivity to cancer therapy.Conclusions:The current study showed that MDM1 expression influences the sensitivity of CRC cells to chemoradiation by influencing p53 and apoptosis pathways,which is the basis for the underlying molecular mechanism,and serves as a possible predictive marker for chemoradiotherapy prognosis.
文摘Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
文摘p53是重要的抑癌基因,在细胞周期阻滞、DNA损伤修复及细胞凋亡等生物过程中发挥重要作用,并已成为潜在的肿瘤治疗靶点。MDM2(Mdm2 p53 binding protein homolog)及MDMX(Mdm4 p53 binding protein homolog)是p53的主要抑制因子,两者相互协同并通过不同的信号途径抑制p53的活性。MDM2是p53的E3连接酶,介导p53的泛素化从而降低p53的稳定性。MD-MX则主要通过与p53的转录活性区结合,抑制p53对其下游基因的转录活性,但并不介导p53的降解。MDM2与MDMX通过不同机制协同对p53产生抑制作用,其具体分子过程及作用机制繁多且复杂。本文就p53。
文摘Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.
