Regulation of the Activity and Stability of the Tumor Suppressor p53 In Vivo

2001 ◽  
Author(s):  
Yang Xo
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor P53

scholarly journals Transglutaminase 2 promotes tumorigenicity of colon cancer cells by inactivation of the tumor suppressor p53

Oncogene ◽  
2021 ◽  
Author(s):  
Patrizia Malkomes ◽  
Ilaria Lunger ◽  
Elsie Oppermann ◽  
Khalil Abou-El-Ardat ◽  
Thomas Oellerich ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Suppressor ◽  
Therapeutic Potential ◽  
Survival Function ◽  
Transglutaminase 2 ◽  
Time Lapse ◽  
Cancer Tissue ◽  
Tumor Suppressor P53 ◽  
Genetic Ablation

AbstractDespite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein–protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.

scholarly journals The Tumor Suppressor p53 Inhibits Net, an Effector of Ras/Extracellular Signal-Regulated Kinase Signaling

2004 ◽  
Vol 24 (3) ◽  
pp. 1132-1142 ◽  
Author(s):  
Koji Nakade ◽  
Hong Zheng ◽  
Gitali Ganguli ◽  
Gilles Buchwalter ◽  
Christian Gross ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Map Kinases ◽  
Specific Gene ◽  
Tumor Suppressor P53 ◽  
Extracellular Signal ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathway

ABSTRACT The tumor suppressor function of p53 is linked to its ability to repress gene expression, but the mechanisms of specific gene repression are poorly understood. We report that wild-type p53 inhibits an effector of the Ras oncogene/mitogen-activated protein (MAP) kinase pathway, the transcription factor Net. Tumor-associated mutant p53s are less efficient inhibitors. p53 inhibits by preventing phosphorylation of Net by MAP kinases. Loss of p53 in vivo leads to increased Net phosphorylation in response to wound healing and UV irradiation of skin. Our results show that p53 can repress specific gene expression by inhibiting Net, a factor implicated in cell cycle entry.

Elucidating genetic events in human hepatocellular carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15590-e15590
Author(s):  
C. Rosario ◽  
R. Gladdy ◽  
M. Ko ◽  
A. Pollett ◽  
J. Dennis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Genetic Interaction ◽  
Tumor Development ◽  
Tumor Formation ◽  
Mutant Mice ◽  
Tumor Suppressor P53 ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded

e15590 Background: Hepatocellular carcinoma (HCC) is prevalent world wide with increasing incidence in North America. 4q is a commonly deleted region in HCC and is lost in 32% of premalignant cirrhotic nodules but the precise molecular lesion involved in tumor initiation remains unknown. Human Plk4, a member of the polo family of cell cycle regulating serine /threonine kinases is located on 4q28. Plk4 is a haploinsufficient tumor suppressor in mice, with 50% of animals developing spontaneous tumors, most commonly multifocal primary HCC. We hypothesize that Plk4 plays a role in the initiation of human HCC. Our purpose was to determine the levels of Plk4 in human HCC and investigate possible genetic interactions with the tumor suppressor p53. Methods: Formalin-fixed paraffin-embedded sections of human HCCs, adjacent non-neoplastic liver tissue and gallbladder tissue were microdissected. DNA was extracted and manual LOH analysis was performed. To asses Plk4 expression, RNA from the hepatoma cases was used for real time RT-PCR. To elucidate a genetic interaction, Plk4 p53 compound mutant mice were generated and murine embryonic fibroblasts (MEFs) were derived and cultured. Results: In HCC Plk4 LOH rates varied from 57% for the marker closest to Plk4 to 8% for the marker furthest away (n=32). Using an intragenic marker the rate of LOH was 45% (n=24). Studies in CRC (n=46) and pancreas cancer specimens (n=40) showed only background levels of LOH. Expression of Plk4 in HCC tumor samples that displayed LOH at the Plk4 locus was reduced compared to non-neoplastic liver. Plk4±p53−/− mice showed acceleration of tumor formation compared to Plk4+/+p53−/− mice. Plk4±p53−/− MEFs had increased levels multinucleation, centrosome amplification and aneuploidy compared to Plk4+/+p53−/− cells. In addition these cells were tumorigenic in vivo whereas Plk4+/+p53−/− cells were not. Conclusions: Our results demonstrate significant rates of LOH at the Plk4 locus specifically in human HCC and indicate that this is associated with decreased Plk4 expression. In addition, our studies of compound mutant mice suggest a possible genetic interaction of Plk4 and p53 in tumor development. No significant financial relationships to disclose.

scholarly journals Literature-based automated discovery of tumor suppressor p53 phosphorylation and inhibition by NEK2

2018 ◽  
Vol 115 (42) ◽  
pp. 10666-10671 ◽  
Author(s):  
Byung-Kwon Choi ◽  
Tajhal Dayaram ◽  
Neha Parikh ◽  
Angela D. Wilkins ◽  
Meena Nagarajan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Scientific Discovery ◽  
Large Body ◽  
Scientific Progress ◽  
Biomedical Literature ◽  
Tumor Suppressor P53 ◽  
Bona Fide ◽  
Automated Discovery

Scientific progress depends on formulating testable hypotheses informed by the literature. In many domains, however, this model is strained because the number of research papers exceeds human readability. Here, we developed computational assistance to analyze the biomedical literature by reading PubMed abstracts to suggest new hypotheses. The approach was tested experimentally on the tumor suppressor p53 by ranking its most likely kinases, based on all available abstracts. Many of the best-ranked kinases were found to bind and phosphorylate p53 (P value = 0.005), suggesting six likely p53 kinases so far. One of these, NEK2, was studied in detail. A known mitosis promoter, NEK2 was shown to phosphorylate p53 at Ser315 in vitro and in vivo and to functionally inhibit p53. These bona fide validations of text-based predictions of p53 phosphorylation, and the discovery of an inhibitory p53 kinase of pharmaceutical interest, suggest that automated reasoning using a large body of literature can generate valuable molecular hypotheses and has the potential to accelerate scientific discovery.

scholarly journals Loss of peptidase D binding restores the tumor suppressor functions of oncogenic p53 mutants

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lu Yang ◽  
Yun Li ◽  
Arup Bhattacharya ◽  
Yuesheng Zhang
Keyword(s):  
Tumor Suppressor ◽  
Cell Fate ◽  
Posttranslational Modifications ◽  
Tumor Suppressor P53 ◽  
Cancer Cell Growth ◽  
Rich Domain ◽  
Cancer Mutation ◽  
Peptidase D

AbstractTumor suppressor p53, a critical regulator of cell fate, is frequently mutated in cancer. Mutation of p53 abolishes its tumor-suppressing functions or endows oncogenic functions. We recently found that p53 binds via its proline-rich domain to peptidase D (PEPD) and is activated when the binding is disrupted. The proline-rich domain in p53 is rarely mutated. Here, we show that oncogenic p53 mutants closely resemble p53 in PEPD binding but are transformed into tumor suppressors, rather than activated as oncoproteins, when their binding to PEPD is disrupted by PEPD knockdown. Once freed from PEPD, p53 mutants undergo multiple posttranslational modifications, especially lysine 373 acetylation, which cause them to refold and regain tumor suppressor activities that are typically displayed by p53. The reactivated p53 mutants strongly inhibit cancer cell growth in vitro and in vivo. Our study identifies a cellular mechanism for reactivation of the tumor suppressor functions of oncogenic p53 mutants.

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