The p53 pathway and human cancer

2005 ◽  
Vol 92 (11) ◽  
pp. 1331-1332 ◽  
Author(s):  
T. Soussi
Keyword(s):  
Human Cancer ◽  
P53 Pathway

scholarly journals SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ziling Fang ◽  
Bo Cao ◽  
Jun-Ming Liao ◽  
Jun Deng ◽  
Kevin D Plummer ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Human Cancer ◽  
Ribosomal Subunit ◽  
P53 Pathway ◽  
Genomic Databases ◽  
Human Cancer Cells ◽  
Ubiquitin Ligase Activity ◽  
Ribosomal Subunit Protein ◽  
P53 Activation ◽  
P53 Inactivation

Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.

scholarly journals Strategies for manipulating the p53 pathway in the treatment of human cancer

2000 ◽  
Vol 352 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Ted R. HUPP ◽  
David P. LANE ◽  
Kathryn L. BALL
Keyword(s):  
Cancer Progression ◽  
Human Cancer ◽  
P53 Protein ◽  
Metastatic Potential ◽  
Biochemical Properties ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
P53 Pathway ◽  
Environmental Pressures ◽  
Human Cancers

Human cancer progression is driven in part by the mutation of oncogenes and tumour-suppressor genes which, under selective environmental pressures, give rise to evolving populations of biochemically altered cells with enhanced tumorigenic and metastatic potential. Given that human cancers are biologically and pathologically quite distinct, it has been quite surprising that a common event, perturbation of the p53 pathway, occurs in most if not all types of human cancers. The central role of p53 as a tumour-suppressor protein has fuelled interest in defining its mechanism of function and regulation, determining how its inactivation facilitates cancer progression, and exploring the possibility of restoring p53 function for therapeutic benefit. This review will highlight the key biochemical properties of p53 protein that affect its tumour-suppressor function and the experimental strategies that have been developed for the re-activation of the p53 pathway in cancers.

scholarly journals Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mannu K Walia ◽  
Patricia MW Ho ◽  
Scott Taylor ◽  
Alvin JM Ng ◽  
Ankita Gupte ◽  
...  
Keyword(s):  
Human Cancer ◽  
Point Mutations ◽  
Therapeutic Targets ◽  
Complete Loss ◽  
Osteoblastic Cells ◽  
Normal Cells ◽  
P53 Pathway ◽  
Common Cancer ◽  
Frequent Event ◽  
Camp Levels

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.

scholarly journals Strategies for manipulating the p53 pathway in the treatment of human cancer

2000 ◽  
Vol 352 (1) ◽  
pp. 1 ◽  
Author(s):  
Ted R. HUPP ◽  
David P. LANE ◽  
Kathryn L. BALL
Keyword(s):  
Human Cancer ◽  
P53 Pathway

scholarly journals The Frizzled-ligand Norrin acts as a tumour suppressor linking oncogenic RAS signalling to p53

2019 ◽  
Author(s):  
Gabriele Sulli ◽  
Errico D’Elia ◽  
M. Cristina Moroni
Keyword(s):  
Human Cancer ◽  
Tumour Progression ◽  
P53 Protein ◽  
Normal Function ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
P53 Pathway ◽  
Genetic Event

AbstractTumour suppressor genes are frequently affected by somatic alterations in cancer, and the impairment of their normal function provides a strong contribution to tumourigenesis. Short-hairpin (sh) RNA library screens have been employed as powerful genetic tools to uncover important new players in human cancer 1–5. To identify potential novel tumour suppressor genes acting in the p53 pathway, we performed an shRNA screen using a cell-based model in which only a single additional genetic event disrupting the p53 pathway is required to obtain in vitro transformation. By using this approach, we report here on the identification of the Frizzled-ligand Norrin (Norrie disease protein) as a candidate tumour suppressor. Inhibition of Norrin expression promotes anchorage-independent growth, confers a strong growth advantage to cells and causes a reduction in p53 protein levels. Conversely, recombinant human Norrin increases p53 levels in a β-catenin dependent fashion. Interestingly, Norrin expression is stimulated by oncogenic H-RAS and BRAF, suggesting that Norrin is part of an early fail-safe mechanism to suppress transformation, and that mutation or down regulation of Norrin could contribute to tumour progression. Indeed, we found that Norrin expression is significantly decreased in melanoma, breast, prostate and ovarian cancer. These findings support the existence of a novel autocrine/paracrine feedback loop that constrains tumourigenesis, in which the crosstalk between the RAS and β–catenin pathways play an unanticipated role.

Two isoprenylated flavonoids from Dorstenia psilurus activate AMPK, stimulate glucose uptake, inhibit glucose production and lower glycemia

2019 ◽  
Vol 476 (24) ◽  
pp. 3687-3704 ◽  
Author(s):  
Aphrodite T. Choumessi ◽  
Manuel Johanns ◽  
Claire Beaufay ◽  
Marie-France Herent ◽  
Vincent Stroobant ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Human Cancer ◽  
Glucose Production ◽  
Liver Mitochondria ◽  
New Drugs ◽  
Structural Isomer ◽  
Rat Liver Mitochondria ◽  
Ionization Mass ◽  
Ampk Activation ◽  
Starting Point

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

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