TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma

Jethwa, Alexander; Słabicki, Mikołaj; Hüllein, Jennifer; Jentzsch, Marius; Dalal, Vineet; Rabe, Sophie; Wagner, Lena; Walther, Tatjana; Klapper, Wolfram; Bohnenberger, Hanibal; Rettel, Mandy; Lu, Junyan; Smits, A.; Stein, Frank; Savitski, Mikhail M.; Huber, Wolfgang; Aylon, Yael; Oren, Moshe; Zenz, Thorsten

doi:10.1182/blood-2017-09-806679

Cited by 30 publications

(33 citation statements)

References 72 publications

(91 reference statements)

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“…Warnock et al [126] also show acetylation of K382 on R273H in multiple colon cancer cell lines (HT29, SW480, SW620). Recently, Jethwa et al [82] have reported that TRRAP, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family which is known to recruit histone acetyltransferases (HATs) to chromatin during transcription and DNA repair [127], increases the levels of multiple TP53 mutants through inhibition of the MDM2-proteasome axis in Burkitt lymphoma (BL-41: R248Q, BL-60: R248Q, CA-46: R248Q, DG-75: R283H/G245S, Namalwa: R248W, Raji: R213Q/Y234H, Ramos: I254D), diffuse large B-cell lymphoma (SUDHL-4: R273H), and colorectal cancer (Colo320: R248W) cell lines. Indeed, upon silencing of TRRAP, acetylation of mutp53 is significantly reduced.…”

Section: Pmts Of Mutp53mentioning

confidence: 99%

Regulators of Oncogenic Mutant TP53 Gain of Function

Yamamoto

Iwakuma

2018

Cancers

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The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.

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Section: Pmts Of Mutp53mentioning

confidence: 99%

Regulators of Oncogenic Mutant TP53 Gain of Function

Yamamoto

Iwakuma

2018

Cancers

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“…Recently, TRRAP was found to be essential for regulating p53 mutant levels in lymphomas by preventing its degradation. [26] Given its enrichment in RCC it may play a potential role to that effect in colorectal cancer.…”

Section: Resultsmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

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To understand the molecular differences between right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer, we analyzed colorectal tumors at the DNA, RNA, miRNA and protein levels using previously sequenced data from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center. Clonal evolution analysis identified the same tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor dynamics and selection of downstream mutations were distinct in all three anatomical locations, with some similarities noted between LCC and rectal cancer. We found a potentially targetable alteration APC R1450* specific to RCC that has not been previously described. Differential gene expression analysis revealed multiple genes within the homeobox, G-protein coupled receptor binding and transcription regulation families were dysregulated in RCC, LCC, and rectal cancers and may have a pathological role in these cancers. Further, using a novel in silico proteomic analytic tool developed by our research group, we found distinct central or hub proteins with unique interactomes in each location. Protein expression signatures were not necessarily concordant with the tumor profiles obtained at the DNA and RNA levels, underscoring the relevance of post-transcriptional events in defining the biology of these cancers beyond molecular changes at the DNA and/or RNA level. Ultimately, not only tumor location and the respective genomic profile but also protein-protein interactions will need to be taken into account to improve treatment outcomes of colorectal cancers. Further studies that take into account the alterations found in this study may help in developing more tailored, and perhaps more effective, treatment strategies.Author summaryPatients with right-sided colon cancer (RCC) has a worse prognosis compared to left-sided colon cancer (LCC). Recent data has also shown that wild-type RAS metastatic RCC’s have poor outcomes when treated with the combination of chemotherapy and anti-EGFR therapy compared to LCC and rectal cancers. Therefore, There is an urgent unmet need to understand the molecular differences between RCC, LCC, and rectal cancers. In this study, we demonstrate clonal evolutionary trajectory and the order of mutations in RCC, LCC, and rectal cancers are distinct with some similarities between LCC and rectal cancers. The order of the mutations that lead to the acquisition of crucial driver alterations may have prognostic and therapeutic implications. We also discovered a novel targetable alteration, APC R1450* to be significantly enriched in early, late and metastatic RCC but not in LCC and rectal cancers. Amazingly, proteomic signatures were discordant with DNA and RNA levels. These distinct differences in DNA, RNA and post-transcriptional events may contribute to their unique clinicopathological features.Conflict of Interest StatementAshiq Masood Advisory board and speaker Bureau Bristol-Myers Squibb and Boehringer IngelheimJanakiraman Subramanian Advisory board - Astra Zeneca, Pfizer, Boehringer Ingelheim, Alexion, Paradigm, Bristol-Myers Squibb Speakers Bureau - Astra Zeneca, Boehringer Ingelheim, Lilly Research Support - Biocept and ParadigmArif Hussain Advisory board – Novartis, Bayer, Astra Zeneca Consultant – Bristol-Myers-Squibb All other authors have no conflict of interest.

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“…By recruitment of TRRAP, c-Myc activates RNA polymerases I and III to control ribosome biogenesis and cell growth. It has been con rmed that TRRAP positively regulates the accumulation of mutant p53 in lymphoma, and TRRAP inhibition by histone deacetylases decreases mutant p53 levels 45 . In addition, TRRAP depletion leads to down-regulation of TOP2A, which is consistent with our results and indicates that the association between these two genes is worthy of exploration in ovarian cancer.…”

Section: Key Genes In the Gene Mutation Analysismentioning

confidence: 99%

Establishment of a prognostic model based on immune infiltration-related genes and clinical information in ovarian cancer

Kong¹,

Zhang²,

Gao³

et al. 2020

Preprint

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Background Ovarian cancer is one of the most lethal gynecological cancers,and is in the top five cancer types associated with death in women. Immune infiltration of ovarian cancer is a critical factor in determining patient's prognosis. In addition to immune infiltration, key mutations also have a greater impact on the development and prognosis of OV.Methods Using data from TCGA and GTEx database combined with WGCNA and ESTIMATE methods, genes related to OV occurrence and immune infiltration were identified. Lasso and multivariate Cox regression were applied to define a prognostic score (IGCI score) based on immune genes and clinical information. The IGCI score has been verified by K-M curves, ROC curves, C-index on test set. Based on mutation data from TCGA, we identified key mutations related to immune infiltration by Chi-squared tests and we also did survival analysis of these mutations.Results In this section, we found 46 genes related to disease occurrence and immune infiltration, IGCI score was established based on six factors: Age, White, Pharmaceutical, FGF7, CCR1 and CD14. In test set, IGCI score (C-index = 0.630) is significantly better than AJCC stage (C-index = 0.541, P < 0.05) and CIN25 (C-index = 0.571, P < 0.05). Chi-squared tests revealed that 6 mutations are significantly (P < 0.05) related to immune infiltration : BRCA1, ZNF462, VWF, RBAK, RB1, and ADGRV1. According to mutation survival analysis, we found another 5 key mutations significantly related to patient prognosis (P < 0.05): CSMD3, FLG2, HMCN1, TOP2A, TRRAP. RB1 and CSMD3 mutations had small p-value (P < 0.1) in both Chi-squared tests and survival analysis. Then we conducted a drug sensitivity analysis of key mutation and found when RB1 mutation occurs, the efficacy of six anti-tumor drugs has changed significantly (P < 0.05).Conclusion Based on immune-related genes and clinical information, we have established an ovarian cancer prognosis score that is superior to other methods. At the same time, RB1 and CSMD3 gene mutations are considered to be closely related to ovarian cancer immunity and prognosis.

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TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma

Cited by 30 publications

References 72 publications

Regulators of Oncogenic Mutant TP53 Gain of Function

Regulators of Oncogenic Mutant TP53 Gain of Function

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Establishment of a prognostic model based on immune infiltration-related genes and clinical information in ovarian cancer

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