Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.
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PMID:Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. 882 21

Papillary carcinoma of the breast is a variant of predominantly intraductal carcinoma characterized by a papillary growth pattern with fibrovascular support. Loss of heterozygosity (LOH) was evaluated at multiple chromosomal loci (including loci reported to show frequent genetic alterations in breast cancer) to determine the frequency of genetic mutations in these tumors and their precursors. Thirty-three papillary lesions of the breast (6 papillary carcinomas, 12 carcinomas arising in a papilloma, and 15 intraductal papillomas with florid epithelial hyperplasia) were retrieved from the files of the Armed Forces Institute of Pathology (AFIP). Tumor cells and normal tissue were microdissected in each case and screened for LOH at INT-2 and p53 as well as several loci on chromosome 16p13 in the TSC2/PKD1 gene region (D16S423, D16S663, D16S665). LOH on chromosome 16p13 was present in 10 of 16 (63%) informative cases of either papillary carcinoma or carcinoma arising in a papilloma as well as in 6 of 10 (60%) informative cases of intraductal papilloma with florid epithelial hyperplasia (IDH). One case showed simultaneous LOH in both the florid IDH and carcinoma components of a papilloma. LOH was not observed at either INT-2 or p53 in any of the papillary carcinomas or papillomas with florid IDH. In conclusion, a high frequency of LOH at chromosome 16p13 (the TSC2/PKD1 gene region) is in both papillary carcinomas of the breast as well as in papillomas with florid IDH, including a case with LOH present simultaneously in both components. These findings suggest that chromosome 16p contains a tumor suppressor gene that frequently is mutated early in papillary neoplasia.
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PMID:LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast. 978 50

Canine hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a rare, naturally occurring inherited cancer syndrome observed in dogs. Genetic linkage analysis of an RCND-informative pedigree has identified a linkage group flanking RCND (CHP14-C05.377-C05.414-FH2383-C05. 771-[RCND-CPH18]-C02608-GLUT4-TP53-ZuBe Ca6-AHT141-FH2140-FH2594) thus localizing the disease to a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (theta) of 0.016, supported by a logarithm of odds score of 16.7. C02608 and the adjacent linked markers map to a region of the canine genome corresponding to portions of human chromosomes 1p and 17p. A combination of linkage analysis and direct sequencing eliminate several likely candidate genes, including tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) and the tumor suppressor gene TP53. These data suggest that RCND may be caused by a previously unidentified tumor suppressor gene and highlight the potential for canine genetics in the study of human disease predisposition.
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PMID:Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs. 1075 51

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
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PMID:Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. 1456 7

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either TSC1 or TSC2 tumor suppressor gene. TSC1 and TSC2 products, Harmatin and Tuberin, form the functional complex to serve as the negative regulator for insulin-induced phosphorylation of S6 kinase and elF4E-binding protein 1. High-risk human papillomavirus (HPV) infection is the necessary cause for cervical cancer. E6 oncoprotein encoded by HPV plays a pivotal role in carcinogenesis by interference with the host intracellular protein functions. In this study, we show that HPV16 E6 interacts with tumor suppressor gene TSC2 product, Tuberin, and results in the phosphorylation of S6 kinase and S6 even in the absence of insulin. The overexpression of Tuberin overcomes the effect of E6 on S6 kinase phosphorylation. Binding with HPV16 E6 causes the proteasome-mediated degradation of Tuberin. A DILG motif and an ELVG motif located in the carboxyl-terminal of Tuberin are required for E6 binding. In addition, the Tuberin interaction region in E6 has been mapped in the amino-terminal portion of HPV16 E6, which is different from the binding domain with p53. These results provide a possible link between E6-induced oncogenesis and the insulin-stimulated cell proliferation signaling pathway.
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PMID:Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin. 1517 23

As many as 5% of human cancers appear to be of hereditable etiology. Of the more than 50 characterized familial cancer syndromes, most involve disease affecting multiple organs and many can be traced to one or more abnormalities in specific genes. Studying these syndromes in humans is a difficult task, especially when it comes to genes that may manifest themselves early in gestation. It has been made somewhat easier with the development of genetically engineered mice (GEM) that phenotypically mimic many of these inheritable human cancers. The past 15 years has seen the establishment of mouse lines heterozygous or homozygous null for genes known or suspected of being involved in human cancer syndromes, including APC, ATM, BLM, BRCA1, BRCA2, LKB1, MEN1, MLH, MSH, NF1, TP53, PTEN, RB1, TSC1, TSC2, VHL, and XPA. These lines not only provide models for clinical disease and pathology, but also provide avenues to investigate molecular pathology, gene-gene and protein-tissue interaction, and, ultimately, therapeutic intervention. Possibly of even greater importance, they provide a means of looking at placental and fetal tissues, where genetic abnormalities are often first detected and where they may be most easily corrected. We will review these mouse models, examine their usefulness in medical research, and furnish sources of animals and references.
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PMID:Mouse models of human familial cancer syndromes. 1520 8

The tumour suppressor gene PTEN is, next to p53, the second most frequently mutated gene in human cancers. The genes TSC1 and TSC2 are mutated in the severe human syndrome called Tuberous Sclerosis. Patients with this disease have large benign tumours composed of large cells in the brain. The genetic dissection of pathways controlling the growth of cells, organs, and the entire organism in Drosophila has contributed to the understanding of the signalling pathways that are controlled by these two tumour suppressors. Together with studies on nutrient regulation of growth and ageing in the nematode Caenorhabditis elegans, evidence from these model organisms has moved the Insulin/IGF (IIS) and the Target Rapamycin (TOR) signalling pathway onto the centre stage of cellular growth control and made them attractive novel targets for cancer therapy. In this review, I will outline the contributions of model organism genetics to the understanding of these disease relevant pathways and highlight the evolutionary conservation of nutrient-dependent growth regulation.
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PMID:Cancer, type 2 diabetes, and ageing: news from flies and worms. 1563 89

Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.
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PMID:The coordinate regulation of the p53 and mTOR pathways in cells. 1592 81

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
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PMID:AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. 1661 76

The downregulation of macroautophagy observed in cancer cells is associated with tumor progression. The regulation of macroautophagy by signaling pathways overlaps with the control of cell growth, proliferation, cell survival and death. Several tumor suppressor genes (PTEN, TSC2 and p53) involved in the mTOR signaling network have been shown to stimulate autophagy. In contrast, the oncoproteins involved in this network have the opposite effect. These findings, together with the discovery that haploinsufficiency of the tumor suppressor beclin 1 promotes tumorigenesis in various tissues in transgenic mice, give credibility to the idea that autophagy is a tumor suppressor mechanism. The induction of macroautophagy by cancer treatments may also contribute to cell eradication. However, cancer cells sometimes mobilize autophagic capacities in response to various stimuli without a fatal outcome, suggesting that they can also exploit macroautophagy for their own benefit.
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PMID:Autophagy signaling and the cogwheels of cancer. 1687 41


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