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)

The aim of this study was to perform a clinical and immunohistochemical comparison between simultaneous independent tumors involving endometrium and ovary and metastatic endometrial tumors, and to try to find clinical and /or immunohistochemical parameters differentiating between these two entities. Sixteen cases of simultaneous independent primaries of endometrium and ovary, presenting the same histologic type, were compared with 12 cases of primary endometrial cancer, demonstrating ovarian metastases. The comparison related to patients' characteristics and immunohistochemical expression of estrogen and progesterone receptors (ER,PR), bcl-2, HER-2 /neu, p53, and cell proliferation marker Ki-67 in endometrial and ovarian tumors. The only clinical parameter differentiating significantly between the groups was the prevalence of familial cancer, being more frequent in the group of metastatic tumors (P = 0.03). Immunohistochemical analysis demonstrated the same immunostaining in endometrium and ovary for all immunohistochemical parameters in cases of metastatic endometrial cancer. Conversely, 62.5% of cases with simultaneous tumors of endometrium and ovary could be differentiated from metastatic tumors by distinct immunohistochemical expression of ER and PR in endometrial and ovarian tumors (P = 0.0006), and 31.3% of cases could be differentiated by distinct immunostaining for bcl-2 (P = 0.03). Immunohistochemical parameters HER-2 /neu, p53 and Ki-67 were not appropriate for the distinction between the two study groups. We conclude that the application of immunohistochemical analysis may play an important role in the differentiation between cases of simultaneous independent carcinomas of endometrium and ovary vs. cases of endometrial carcinoma with ovarian metastases.
 ...
PMID:Simultaneous carcinoma of the endometrium and ovary vs endometrial carcinoma with ovarian metastases: a clinical and immunohistochemical determination. 1263 Dec 17

Epidemiological studies over the past several decades have consistently supported the concept that a proportion of breast cancers develop as the result of an inherited familial predisposition. However, until recently our understanding and knowledge of the underlying genetic processes involved have been limited. Current advances in molecular biology have shown that hereditary breast cancer may arise as the result of mutations of several specific gene loci including BRCA1, BRCA2, ATM gene, PTEN and p53. Several other less frequently occurring predisposition genes such as the androgen receptor gene (AR), the HNPCC genes and the oestrogen receptor gene may also be involved, but to a lesser extent. It is estimated that approximately 5-10% of all breast cancers involve one of these inherited predisposition genes, with BRCA1 and BRCA2 accounting for up to 90% of this group. Mutation analysis is complex in nature and is presently in a developmental and evolving phase, for which reason genetic testing should be offered on a selective basis and through genetic counselling clinics. This report reviews the current knowledge and roles of the various predisposition genes and discusses the management implications for both affected and nonaffected members of breast cancer families. Comprehensive and informative counselling is critical for women with an inherited predisposition to breast cancer and this has led to the evolution of familial cancer clinics involving a multi-disciplinary specialist team approach. Familial cancer clinics can provide individuals with information about their risk of developing breast cancer and offer advice regarding the various management options presently available.
 ...
PMID:The management of familial breast cancer. 1473 74

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.
 ...
PMID:Mouse models of human familial cancer syndromes. 1520 8

Multiple early-onset tumors, frequently associated with germ line TP53 mutations characterize the Li-Fraumeni familial cancer syndrome (LFS). LFS-like (LFS-L) families have lower rates of germ line TP53 alteration and do not meet the strict definition of LFS. This study examined 7 LFS cell lines and 30 LFS and 36 LFS-L primary leukocyte samples for mutations in the proapoptotic p53-regulated gene BAX. No germ line BAX mutations were found. A known BAX polymorphism was observed, yet there was no correlation between polymorphism frequency and TP53 status in either LFS or LFS-L. In summary, alterations of BAX are not responsible for cancers in TP53 wild-type LFS or LFS-L families.
 ...
PMID:Germ line BAX alterations are infrequent in Li-Fraumeni syndrome. 1529 65

Li-Fraumeni syndrome is a familial cancer syndrome characterized by different tumors and hereditary p53 mutations. Here, a chronic myeloid leukemia-like syndrome case in a Li-Fraumeni syndrome family with del (12) (p12) cytogenetic abnormality was presented. A hereditary p53 mutation (pro309ser) supported the Li-Fraumeni syndrome diagnosis in this family. This syndrome was characterized by the clonal myeloproliferative accumulation in bone marrow and peripheral blood with negative bcr/abl gene rearrangement finding. The etiology of this rare syndrome is still unclear. This is the only chronic myeloid leukemia-like syndrome case reported in a Li-Fraumeni syndrome family. Del (12)(p12) was observed in leukemias except chronic myeloid leukemia-like syndrome. The deletion in chromosome 12p12 with hereditary p53 mutation should have a critical role in chronic myeloid leukemia-like syndrome etiology in our case.
 ...
PMID:A chronic myeloid leukemia-like syndrome case with del (12) (p12) in a Li-Fraumeni syndrome family. 1578 29

A haploid genotype may be insufficient to support normal wild-type function. Such haplo-insufficiency has recently been documented for numerous tumour suppressor genes. p53 is a crucial tumour suppressor governing DNA repair, cell cycle arrest and apoptosis via its role as a stress-responsive transcription factor. p53 haplo-insufficiency has been observed in vivo with human familial cancer in Li-Fraumeni Syndrome (LFS) and in mouse p53-knockout models of LFS. The increased tumorigenesis associated with loss of one p53 allele has been attributed to reduced p53-dependent stress responses. However, the underlying biochemical basis for such attenuated responses in p53+/- cells remains unclear. Here we have determined basal p53 messenger RNA (mRNA) and protein levels, and compared the p53 stress response in p53+/+, p53+/- and p53-/- isogenic clones derived from HCT116 cells. Basal expression of p53 in p53+/- cells was 25% relative to p53+/+ cells, and this differential was maintained following oncogenic stress. This deficiency was manifested at both p53 mRNA and protein levels and resulted in attenuated p53 stress responses, in particular for p21waf1 upregulation and survivin downregulation, and reduced G1 arrest and apoptosis. These observations identify a molecular basis for wild-type p53 haplo-insufficiency, which may explain the attenuated tumour-suppressive phenotype observed in cells with a single wild-type p53 allele and in humans with LFS.
 ...
PMID:Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency. 1644 74

Hotspot mutations in the p53 tumor suppressor gene result in the disruption of DNA contact points or alter the overall structure of the protein to prevent DNA binding. When inherited, hotspot mutants are associated with Li-Fraumeni syndrome (LFS), a familial cancer predisposition. One of the most common hotspot mutations occurs at codon 175, resulting in an arginine to histidine substitution. We have identified a novel germ line variant of the 175 mutant (Arg to Leu; R175L) in a pediatric patient who developed adrenal cortical carcinoma. Surprisingly, the family is not tumor prone or associated with LFS. In vitro, the R175L mutant displayed an attenuated tumor suppressor activity in the regulation of transcription, colony formation, and apoptosis when compared with wild-type p53 and the R175H mutant. These findings suggest that p53-R175L retains sufficient activity to suppress LFS, but not adrenal cortical carcinoma. Therefore, not all hotspot mutants are functionally equivalent and the biochemical nature of the mutant may significantly influence clinical outcome. The implications of these results for genetic counseling are discussed.
 ...
PMID:Identification of a novel germ line variant hotspot mutant p53-R175L in pediatric adrenal cortical carcinoma. 1670 27

Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma.
 ...
PMID:Inducible and transmissible genetic events and pediatric tumors of the nervous system. 1701 46

Osteosarcoma is a devastating but rare disease, whose study has illuminated both the basic biology and clinical management of cancer over the past 30 years. These contributions have included insight into the roles of key cancer genes such as the retinoblastoma tumor suppressor gene and TP53, the identification of familial cancer syndromes implicating DNA helicases, and dramatic improvements in survival by the use of adjuvant chemotherapy. This review provides a synoptic overview of our current understanding of the molecular causes of osteosarcoma, and suggests future directions for study.
 ...
PMID:Molecular pathogenesis of osteosarcoma. 1726 92

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT constitute an important pathway regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase and its main substrate phosphatidyl-inositol 3,4,5 triphosphate (PIP3) is the product of PI3K. Increase in PIP3 recruits AKT to the membrane where is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germ line mutations of PTEN are found in several familial cancer predisposition syndromes. Recently, many activating mutations in the PI3KCA gene (coding for the p110alpha catalytic subunit of PI3K) have been described in human tumors. Activation of PI3K and AKT are reported to occur in breast, ovarian, pancreatic, esophageal and other cancers. Genetically modified mice confirm these PTEN activities. Tissue-specific deletions of PTEN usually provoke cancer. Moreover, an absence of PTEN cooperates with an absence of p53 to promote cancer. However, we have observed very different results with the expression of activated versions of AKT in several tissues. Activated AKT transgenic lines do not develop tumors in breast or prostate tissues and do not cooperate with an absence of p53. This data suggest that an AKT-independent mechanism contributes to PTEN tumorigenesis. Crosses with transgenic mice expressing possible PTEN targets indicate that neither cyclin D1 nor p53 are these AKT-independent targets. However, AKT is more than a passive bridge toward PTEN tumorigenesis, since its expression not only allows but also enforces and accelerates the tumorigenic process in combination with other oncogenes.
 ...
PMID:PTEN, more than the AKT pathway. 1734 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>