scholarly journals Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis

2018 ◽  
Vol 217 (7) ◽  
pp. 2353-2363 ◽  
Author(s):  
Carla A.M. Lopes ◽  
Marta Mesquita ◽  
Ana Isabel Cunha ◽  
Joana Cardoso ◽  
Sara Carapeta ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Human Cancer ◽  
Centrosome Amplification ◽  
Loss Of Function ◽  
Tumor Suppressor P53 ◽  
Cancer Model ◽  
Wild Type ◽  
Representative Cell ◽  
Premalignant Condition ◽  
Hotspot Mutations

Centrosome abnormalities are a typical hallmark of human cancers. However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in Barrett’s esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the premalignant condition to the metastatic disease. This human cancer model allows the study of sequential steps of progression within the same patient and has representative cell lines from all stages of disease. Remarkably, centrosome amplification was detected as early as the premalignant condition and was significantly expanded in dysplasia. It was then present throughout malignant transformation both in adenocarcinoma and metastasis. The early expansion of centrosome amplification correlated with and was dependent on loss of function of the tumor suppressor p53 both through loss of wild-type expression and hotspot mutations. Our work shows that centrosome amplification in human tumorigenesis can occur before transformation, being repressed by p53. These findings suggest centrosome amplification in humans can contribute to tumor initiation and progression.

scholarly journals The tumor suppressor p53 promotes carcinoma invasion and collective cellular migration

2018 ◽  
Author(s):  
Shijie He ◽  
Christopher V. Carman ◽  
Jung Hyun Lee ◽  
Bo Lan ◽  
Stephan Koehler ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Colorectal Carcinoma ◽  
Cell Motility ◽  
Single Cell ◽  
Cell Layer ◽  
Carcinoma Cells ◽  
Cellular Migration ◽  
Loss Of Function ◽  
Tumor Suppressor P53 ◽  
Increase Cell Motility

SummaryLoss of function of the tumor suppressor p53 is generally thought to increase cell motility and invasiveness. Using 2-D confluent and 3-D spheroidal cell motility assays with bladder carcinoma cells and colorectal carcinoma cells, we report, to the contrary, that loss of p53 can decrease cell motility and invasion.AbstractFor migration of the single cell studied in isolation, loss of function of the tumor suppressor p53 is thought to increase cell motility. Here by contrast we used the 2-D confluent cell layer and the 3-D multicellular spheroid to investigate how p53 impacts dissemination and invasion of cellular collectives. We used two human carcinoma cell lines, the bladder carcinoma EJ and the colorectal carcinoma HCT116. We began by replicating single cell invasion in the traditional Boyden chamber assay, and found that the number of invading cells increased with loss of p53, as expected. In the confluent 2-D cell layer, however, for both EJ and HCT, speeds and effective diffusion coefficients for the p53 null types compared to their p53 expressing counterparts were significantly smaller. Compared to p53 expressers, p53 null cells exhibited more organized cortical actin rings together with reduced front-rear cell polarity. Furthermore, loss of p53 caused cells to exert smaller traction forces upon their substrates, and reduced formation of cryptic lamellipodia. In a 3-D collagen matrix, p53 consistently promoted invasion of the multicellular spheroids into surrounding matrix. Together, these results show that p53 expression in these carcinoma model systems increases collective cellular migration and invasion. As such, these studies point to paradoxical contributions of p53 in single cell versus collective cellular migration.

scholarly journals Toward Cancer Diagnostics of the Tumor Suppressor p53 by Surface Enhanced Raman Spectroscopy

Sensors ◽  
2020 ◽  
Vol 20 (24) ◽  
pp. 7153
Author(s):  
Anna Rita Bizzarri ◽  
Salvatore Cannistraro
Keyword(s):  
Raman Spectroscopy ◽  
Tumor Suppressor ◽  
P53 Protein ◽  
Surface Enhanced Raman Spectroscopy ◽  
Cancer Diagnostics ◽  
Clinical Diagnostics ◽  
Tumor Suppressor P53 ◽  
Wild Type ◽  
Surface Enhanced ◽  
Surface Enhanced Raman

The tumor suppressor p53 protein plays a crucial role in many biological processes. The presence of abnormal concentrations of wild-type p53, or some of its mutants, can be indicative of a pathological cancer state. p53 represents therefore a valuable biomarker for tumor screening approaches and development of suitable biosensors for its detection deserves a high interest in early diagnostics. Here, we revisit our experimental approaches, combining Surface Enhanced Raman Spectroscopy (SERS) and nanotechnological materials, for ultrasensitive detection of wild-type and mutated p53, in the perspective to develop biosensors to be used in clinical diagnostics. The Raman marker is provided by a small molecule (4-ATP) acting as a bridge between gold nanoparticles (NPs) and a protein biomolecule. The Azurin copper protein and specific antibodies of p53 were used as a capture element for p53 (wild-type and its mutants). The developed approaches allowed us to reach a detection level of p53 down to 10−17 M in both buffer and serum. The implementation of the method in a biosensor device, together with some possible developments are discussed.

scholarly journals Ceramide modulates pre-mRNA splicing to restore the expression of wild-type tumor suppressor p53 in deletion-mutant cancer cells

2014 ◽  
Vol 1841 (11) ◽  
pp. 1571-1580 ◽  
Author(s):  
Gauri A. Patwardhan ◽  
Salman B. Hosain ◽  
David X. Liu ◽  
Sachin K. Khiste ◽  
Yunfeng Zhao ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Deletion Mutant ◽  
Mrna Splicing ◽  
Tumor Suppressor P53 ◽  
Wild Type

scholarly journals Elevated MCOLN1 Expression in p53-Deficient Bladder Cancer is Necessary for Oncogene-Induced Cell proliferation, Inflammation, and Invasion

2020 ◽  
Author(s):  
Jewon Jung ◽  
Han Liao ◽  
Hong Liang ◽  
John F. Hancock ◽  
Catherine Denicourt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bladder Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Cytokine Production ◽  
Urothelial Cells ◽  
Tumor Suppressor P53 ◽  
Wild Type ◽  
Bladder Cancer Cells

SummaryInhibition of the endolysosomal cation channel, TRPML1, which is encoded by MCOLN1, deters the proliferation of cancer cells with augmented TFEB activity. Here, we report that the tumor suppressor, p53, antagonizes TFEB-driven MCOLN1 expression in bladder cancer. Not only was the constitutive loss of p53 in bladder cancer cells associated with higher MCOLN1 mRNA, knockdown of TP53 in lines with wild type alleles of the tumor suppressor increased MCOLN1 expression. Elevated TRPML1 abundance in p53-deficient cancer cells, although not sufficient for bolstering proliferation, was necessary for the effects of oncogenic HRAS on cell division, cytokine production, and invasion. These data demonstrate that hyperactivation of the TFEB– MCOLN1 transcriptional axis in urothelial cells lacking p53 permits tumorigenesis stemming from HRAS mutations. Furthermore, the insight that loss of p53 predicts addiction to TRPML1 informs an actionable therapeutic strategy for bladder cancer.

scholarly journals Suppression of EZH2 Accelerates MYC-Driven Lymphomagenesis By Inhibition of Apoptosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3009-3009 ◽  
Author(s):  
Iris Appelmann ◽  
Claudio Scuoppo ◽  
Vishal Thapar ◽  
Daniela Ledezma ◽  
Amaia Lujambio ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Human Cancer ◽  
B Cell Lymphoma ◽  
Metastatic Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
Proliferating Cells ◽  
Gain Of Function

Abstract EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), which also contains the non-catalytic subunits suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). This complex methylates histone H3 at lysine 27 (H3K27) which, together with H3K4 methylation, generates a bivalent “code” that primes genes for either expression or silencing. EZH2 is highly expressed in stem cells and many proliferating cells, downregulated in differentiated cells and frequently altered in cancer in ways that point to a context dependent role for this gene. For instance, overexpression of EZH2 has been described in prostate and breast cancer, where this overexpression is associated with invasive growth metastatic potential and poor clinical outcome. More recently, both gain and loss of function mutations of EZH2 were identified in human cancer. In particular, activating mutations of EZH2 affecting a tyrosine at position 641 located within the SET domain (Y641) were observed in lymphoma. In striking contrast to wild type EZH2 which catalyzes the monomethylation of H3K27 very efficiently and shows less efficient catalytic activity in the subsequent di- and trimethylation reactions, the mutation generates a neomorphic protein with enhanced catalytic activity and efficiency for di- and tri-methylation, hinting toward a “cooperation” of both wild type and mutant EZH2 to increase total H3K27me3 levels and representing a functional equivalent of EZH2 overexpression in human lymphoma. Gain of function mutations in EZH2 are frequent in Diffuse Large B-cell Lymphoma (DLBCL; 22%) and in Follicular Lymphoma (FL; 7%) and recent data implicate EZH2 as an oncogene in DLBCL and FL lymphomas. In contrast to DLBCL and FL, EZH2 mutations have so far never been identified in MYC-driven B-cell Non-Hodgkin Lymphoma (B-NHL), and EZH2 expression is suppressed in Burkitt’s Lymphoma (BL), a lymphoma for which a MYC translocation is pathognomonic, suggesting that in this context EZH2 could have a role different from its role in DLBCL and FL. We probed the role of EZH2 in MYC-driven lymphomagenesis by mimicking the loss of function mutations by RNAi mediated suppression of EZH2 and the gain of function mutations by over-expression of the Y641 mutant. Our results show that suppression of EZH2, but not overexpression of the EZH2 Y641 mutant, accelerates MYC-driven lymphomagenesis by attenuating apoptosis. Our model recapitulates the transcriptional signature of a subset of B-NHLs driven by MYC overactivation and EZH2 suppression. Taken together, our data imply EZH2 as a tumor suppressor in the context of MYC activation and thus raise a warning for the use of EZH2-targeted therapies in some B-NHLs subtypes. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Cross Talk Between p53 and mTOR Pathways in Response to Physiological and Genotoxic Stresses

2021 ◽  
Vol 9 ◽  
Author(s):  
Danrui Cui ◽  
Ruirui Qu ◽  
Dian Liu ◽  
Xiufang Xiong ◽  
Tingbo Liang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Current Knowledge ◽  
Human Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Tumor Suppressor P53 ◽  
Induce Cell Cycle Arrest ◽  
Downstream Effectors ◽  
Cellular Stresses

The tumor suppressor p53 is activated upon multiple cellular stresses, including DNA damage, oncogene activation, ribosomal stress, and hypoxia, to induce cell cycle arrest, apoptosis, and senescence. Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, serves as a central regulator of cell growth, proliferation, and survival by coordinating nutrients, energy, growth factors, and oxygen levels. p53 dysfunction and mTOR pathway hyperactivation are hallmarks of human cancer. The balance between response to stresses or commitment to cell proliferation and survival is governed by various regulatory loops between the p53 and mTOR pathways. In this review, we first briefly introduce the tumor suppressor p53 and then describe the upstream regulators and downstream effectors of the mTOR pathway. Next, we discuss the role of p53 in regulating the mTOR pathway through its transcriptional and non-transcriptional effects. We further describe the complicated role of the mTOR pathway in modulating p53 activity. Finally, we discuss the current knowledge and future perspectives on the coordinated regulation of the p53 and mTOR pathways.

scholarly journals An antisense RNA capable of modulating the expression of the tumor suppressor microRNA-34a

2017 ◽  
Author(s):  
Jason T. Serviss ◽  
Felix Clemens Richter ◽  
Jimmy Van den Eynden ◽  
Nathanael Andrews ◽  
Miranda Houtman ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Antisense Rna ◽  
Human Cancer ◽  
Cellular Growth ◽  
Wild Type ◽  
Cellular Functions ◽  
Downstream Target ◽  
Non Coding Rna ◽  
Different Types ◽  
Long Non Coding Rna

AbstractThe microRNA-34a is a well-studied tumor suppressor microRNA (miRNA) and a direct downstream target of TP53 with roles in several pathways associated with oncogenesis, such as proliferation, cellular growth, and differentiation. Due to its broad tumor suppressive activity, it is not surprising that miR34a expression is altered in a wide variety of solid tumors and hematological malignancies. However, the mechanisms by which miR34a is regulated in these cancers is largely unknown. In this study, we find that a long non-coding RNA transcribed antisense to the miR34a host gene, is critical for miR34a expression and mediation of its cellular functions in multiple types of human cancer. We name this long non-coding RNA lncTAM34a, and characterize its ability to facilitate miR34a expression under different types of cellular stress in both TP53 deficient and wild type settings.

scholarly journals Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells

2013 ◽  
Vol 41 (11) ◽  
pp. 5614-5625 ◽  
Author(s):  
Ji Young Lee ◽  
Hyo Jeong Kim ◽  
Nal Ae Yoon ◽  
Won Hyeok Lee ◽  
Young Joo Min ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Human Cancer ◽  
Tumor Suppressor P53 ◽  
Human Cancer Cells

PML Controls PTEN Localization and Function in APL through a Novel Deubiquitination Pathway

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3812-3812
Author(s):  
Arkaitz Carracedo ◽  
MIn-Sup Song ◽  
Leonardo Salmena ◽  
Ainara Egia ◽  
Francesco Lo-Coco ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Solid Tumors ◽  
Nuclear Localization ◽  
Human Cancer ◽  
Adaptor Protein ◽  
Pi3k Pathway ◽  
Genetically Engineered ◽  
Human Leukemia ◽  
Death Domain ◽  
Loss Of Function

Abstract PML was discovered as a gene frequently involved in the t(15:17) translocation of acute promyelocytic leukemia (APL). Since then, consequences of PML-loss of function in APL and other solid tumors have been extensively studied. Numerous pathways influenced by this tumor suppressor, including the PI3K pathway, have been identified but their importance for the pathogenesis APL is still unclear. We have now discovered that PTEN, the main tumor suppressor opposing PI3K signaling, is aberrantly delocalized to the cytoplasm in APL, but not in AML. Moreover, we show that drugs such as arsenic trioxide and retinoic acid, currently used for the treatment of APL and known to target the oncogenic PML-RARalpha fusion protein, rescue the nuclear localization of PTEN. This discovery has critical biological implications since nuclear localization of PTEN is central to its tumor suppressive activity. Utilizing an APL cell line, genetically engineered cells and transgenic mice, we have delineated the mechanism by which PML sustains nuclear PTEN. PML opposes the activity of a novel PTEN-deubiquitinating enzyme, HAUSP, towards PTEN through a framework involving the adaptor protein DAXX (death domain-associated protein). We demonstrate that PML-RARalpha translocation results in overactive HAUSP and as a consequence, nuclear-excluded PTEN. In support of this notion, we show that HAUSP is overexpressed in human cancer, (e.g. in prostate cancer) which is in turn associated with a nuclear exclusion phenotype of PTEN. Overall our results describe a novel role for PML in the maintenance of PTEN function that is perturbed by oncogenic cues in human leukemia and solid tumors. Significantly, our findings open new avenues for the design of targeted therapies focused on potentiating the activity of the PML-PTEN tumor suppressive network.

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