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)

Specific abnormalities in cancers are the best molecular targets of therapeutics, which is exemplified by trastuzumab. ERBB2 amplification is present in 15-30% of invasive ductal carcinomas, and its overexpression was associated with poor prognosis. c-MYC amplification is present in 13-19%, but other forms of oncogene activation are rare. Germline mutations of BRCA1 and BRCA2 are responsible for familial breast cancers. Their somatic mutations in sporadic breast cancers are rare, but chromosomal losses are frequent. Inactivation of BRCA1 by its promoter methylation is also frequent. p53 mutations are present in 20-25% of sporadic breast cancers, and inactivation of its pathway is present in most of them. Further molecular analysis will reveal new targets for diagnosis and therapeutics.
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PMID:[Genes involved in breast cancers]. 1652 32

Small cell osteosarcoma is a rare bone tumor of high-grade malignancy that most often arises in the metaphysis of long bones in the second decade of life. Cytogenetic and molecular genetic findings in small cell osteosarcoma are poorly defined. Conventional cytogenetic analysis of a small cell osteosarcoma arising in the proximal tibia of a 9-year-old male revealed a diploid chromosomal complement with complex structural rearrangements involving chromosomes 6, 16, and 17. Immunohistochemical assessment of p53 protein expression revealed nuclear p53 immunoreactivity in approximately 15% of the neoplastic cells. Subsequent fluorescence in situ hybridization (FISH) analyses confirmed loss of the p53 gene locus on the derivative chromosome 17 homolog and were negative for amplification of the MDM2, CDK4, c-MYC, HER-2/neu, CCND1, and COPS3 gene loci. To the best of our knowledge, this represents the first demonstration of monoallelic deletion of p53 in small cell osteosarcoma, suggesting that p53 alterations may play an important role in the development of small cell osteosarcoma as well as conventional osteosarcoma.
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PMID:Monoallelic deletion of the p53 gene through chromosomal translocation in a small cell osteosarcoma. 1659 82

We present a case of leukemic mantle cell lymphoma with cryptic and complex chromosomal rearrangements, including multiple-way translocations involving chromosomes 8q24, 14q11/q32, 17p13.3, 17p13.1, 21q22, and 21q22; a deletion of the long arm of chromosome 10 [del(10)(q24)]; and a deletion of the TP53 gene in addition to t(11;14). We speculate that this series of chromosomal changes may disrupt the IgH gene, activate the c-MYC oncogene, inactivate the p53 tumor suppressor gene, and disrupt other cancer-related genes either within or flanking the chromosomal breakpoints. This combinational effect causes the progression of mantle cell lymphoma.
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PMID:Cryptic and complex chromosomal rearrangements and the deletion of TP53 gene in a patient with leukemic mantle cell lymphoma. 1693 77

In response to various forms of cellular stress, including DNA damage, ribonucleotide depletion, and abnormal proliferative signals, p53 becomes activated as a transcription factor, targeted genes that induce cell-cycle arrest and apoptosis. Eliminating damaged, stressed, or abnormally proliferating cells from the replicating cell population prevents the propagation of potentially cancer-prone cells. Here we focus on the transcriptional targets of p53 that regulate the cell cycle. p53 Induction of G1/ S cell-cycle arrest is largely attributed to the transcriptional upregulation of p21WAF1, and more recently, to the transcriptional repression of c-MYC. The role of p53 in G2/M cell-cycle arrest in response to DNA damage is more complex, involving multiple targets that can generally be considered to impinge upon either the cell cycle (e.g., Cyclin-B, cdc2, cdc25C) or the mitotic machinery (i.e., Topoisomerase II, B99/Gtse-1, and MAP4). The ability of p53 to regulate these two type of gene targets may reflect p53-mediated early versus late events in the G2/M cell-cycle arrest response. Together the information presented illustrates the need for further studies to precisely delineate the nature of G2/M cell-cycle arrest in response to cell stress, and defines the role of p53 in what is likely an important mechanism of tumor suppression.
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PMID:Transcriptional targets of p53 that regulate cellular proliferation. 1736 86

TIP30 is a tumor suppressor whose expression is altered in human liver, prostate, lung, colon, and breast cancers. Mice lacking TIP30 spontaneously developed hepatocellular carcinomas (HCC) and other tumors at a higher incidence than wild-type mice. Somatic missense mutations in the TIP30 gene were identified in human HCC tissue specimens, which resulted in instability or abnormal cellular distribution of TIP30 protein in cells. Here, we show that TIP30 mutants are able to promote cell growth and invasion and inhibit cisplatin-induced apoptosis in the HCC cell line HepG2 negative for endogenous TIP30. Moreover, one of the TIP30 mutants can dramatically accelerate tumor formation in immunodeficient mice. Analysis of gene expression in HepG2 cells, ectopically expressing either wild-type TIP30 or mutant TIP30, by Affymetrix GeneChip array, real-time quantitative PCR, and Western blotting assays reveals that TIP30 mutants can alter expression of genes involved in the regulation of tumorigenesis. This includes up-regulation of expression of N-cadherin and c-MYC and down-regulation of expression of p53 and E-cadherin. N-cadherin knockdown with small interfering RNA in HepG2 cells expressing mutant TIP30 resulted in a profound reduction in cell viability. Taken together, our data indicate that somatic mutations in the TIP30 gene may abolish its native tumor-suppressor activity and gain oncogenic activities partially through up-regulation of N-cadherin, thereby potentiating the pathogenesis of HCC in patients.
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PMID:TIP30 mutant derived from hepatocellular carcinoma specimens promotes growth of HepG2 cells through up-regulation of N-cadherin. 1744 68

Meningiomas, which originate from arachnoid cells and constitute the largest subgroup of all intracranial tumors, are generally benign, yet have the capacity to progress into a higher histological grade of malignancy associated with an increase in biological aggressivity and/or capacity to recur. To elucidate meningioma pathogenesis and malignancy, we applied a holistic and network approach analyzing cDNA and tissue microarray results. A potential pathway leading to meningioma angiogenesis, apoptosis and proliferation was evidenced as well as a regulatory network of the biomarkers including Ki-67, AR, CD34, P53, c-MYC, etc. which might support clinical research. In this potential pathway, ITGB1 could be the most important "superoncogene" playing a vital role in apoptosis and proliferation, while FOXO3A, MDM4 and MT3 are important to the malignancy process. Some genes are first reported that could explain why radiation induces meningioma and why more female than male patients are affected. Further, we present the hypothesis that HIV-Tat protein might have a close relationship with meningioma pathogenesis and malignancy.
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PMID:Holistic and network analysis of meningioma pathogenesis and malignancy. 1747 81

Although human papillomavirus (HPV) infections are the primary cause of cervical cancer, the molecular mechanism by which HPV induces cervical cancer remains largely unclear. We used two-dimensional electrophoresis with mass spectrometry to study protein expression profiling between HPV16-positive cervical mucosa epithelial H8 cells and cervical cancer Caski cells to identify 18 differentially expressed proteins. Among them, retinoblastoma-binding protein 4 (RbAp48) was selected, and its differentiation expression was verified with both additional cervical cancer-derived cell lines and human tissues of cervical intraepithelial neoplasia and cervical cancer. Suppression of RbAp48 using small interfering RNA approach in H8 cells significantly stimulated cell proliferation and colony formation and inhibited senescence-like phenotype. Remarkably, H8 cells acquired transforming activity if RpAp48 was suppressed, because H8 cells stably transfected with RbAp48 small interfering RNA led to tumor formation in nude mice. In addition, overexpression of RbAp48 significantly inhibited cell growth and tumor formation. This RbAp48-mediated transformation of HPV16 is probably because of the regulation by RbAp48 of tumor suppressors retinoblastoma and p53, apoptosis-related enzymes caspase-3 and caspase-8, and oncogenic genes, including E6, E7, cyclin D1 (CCND1), and c-MYC. In brief, RbAp48, previously unknown in cervical carcinogenesis, was isolated in a global screen and identified as a critical mediator controlling the transforming activity of HPV16 in cervical cancer.
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PMID:RbAp48 is a critical mediator controlling the transforming activity of human papillomavirus type 16 in cervical cancer. 1761 26

N-MYC encodes a basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor that is frequently overexpressed in human neuroblastoma. N-MYC overexpression has also been reported in human acute myeloid leukemias (AML), which we show here is a frequent event. Myeloid cells in N-Myc-overexpressing mouse bone marrow hyperproliferate but those in c-MYC-overexpressing bone marrow do not. The NH(2)-terminal transactivation domain, nuclear localization signal, and bHLH/LZ domain of N-Myc are essential for this effect. Microarray analysis revealed 969 differentially expressed genes between N-Myc- and c-MYC-overexpressing myeloid cells. N-Myc-overexpressing cells showed decreased transforming growth factor beta signaling and increased c-Jun-NH(2)-kinase signaling, both of which are associated with proliferation and leukemic transformation of myeloid cells. Mice transplanted with bone marrow expressing wild-type N-Myc developed clonal and transplantable AML after approximately 1 month; those transplanted with bone marrow expressing mutant N-Myc did not. Twist, a known suppressor of the p19Arf/p53 pathway, was up-regulated in all tumors. These results show that N-Myc overexpression is highly oncogenic in mouse myeloid cells and suggest that N-MYC up-regulation contributes to human myeloid leukemogenesis.
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PMID:Overexpression of N-Myc rapidly causes acute myeloid leukemia in mice. 1800 9

The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1alpha, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.
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PMID:Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. 1804 11

The c-MYC proto-oncogene encodes a transcription factor that is critical for cell growth and proliferation. It is one of the genes frequently altered in cancer cells in which it exhibits constitutive activity. The half-life of c-MYC is very short in quiescent cells due to ubiquitin-mediated proteolysis. We report here the rapid and dose-dependent decline of c-MYC protein level after UV-irradiation in various human and rodent cells. This decline is due to a proteasomal degradation of c-MYC protein and does not require the binding sites for the FBW7 and SKP2 ubiquitin ligases. Together, our data exclude a prominent role for the stress-responsive kinase PAK2, for the major phosphoinositide 3-kinase related protein kinases ATR, ATM, DNA-PK and mTOR and for ERK, JNK and p38 mitogen activated protein kinases in this UV-induced degradation process. We propose that c-MYC degradation is part of the global cell response to UV-damage, complementary to the accumulation and activation of the p53 transcription factor. By contributing to the replication arrest after infliction of lesions to the genome, the induced degradation of c-MYC may be part of the safeguard mechanisms maintaining genome stability.
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PMID:c-MYC protein is degraded in response to UV irradiation. 1819 73


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