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

Germ line mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) with a predisposition to cancer. Previous reports suggest that inactivation of this tumor-suppressor gene plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including adenocarcinoma of the pancreas. Here, we have shown that LKB1 gene is silenced in the pancreatic cancer cell line AsPC-1, but can be recovered by treatment with the methylation inhibitor, 5-aza-2'-deoxycytidine (5aza2dC). Restoring the level of LKB1 through gene transfer initiated mitochondria-mediated apoptosis in AsPC-1 cells, as evidenced by the release of cytochrome c from the mitochondria. By confocal microscopy as well as biochemical fractionation, we demonstrate that LKB1 is present in the nuclear and mitochondrial compartments of pancreatic cancer cells. Our observations also indicate that although functional p53 is absent, the p53 kin, p73, is inducible by doxorubicin in AsPC-1 cells. This suggests that LKB1-induced apoptosis is p53 independent but might be p73-mediated in the pancreatic tumor cell line, AsPC-1.
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PMID:Restoration of silenced Peutz-Jeghers syndrome gene, LKB1, induces apoptosis in pancreatic carcinoma cells. 1451 8

It is estimated that 5%-10% of all breast cancers in women are associated with hereditary susceptibility due to mutations in autosomal dominant genes, such as BRCA1 and BRCA2, p53, pTEN, and STK11/LKB1. Another 15%-20% of female breast cancers occur in women with a family history but without an apparent autosomal dominant inheritance pattern, and are probably due to other genetic factors with environmental influence. Approximately 7%-10% of ovarian cancers occur in women with hereditary susceptibility, primarily secondary to mutations in BRCA1 and BRCA2, with smaller contributions from mutations in mismatch repair genes associated with the hereditary nonpolyposis colorectal cancer and other, as yet undiscovered, genes.
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PMID:Genetics and the management of women at high risk for breast cancer. 1453 May

The tumour suppressor gene, LKB1/STK11, has been mapped to chromosome 19p13, a region showing frequent allelic loss in various human cancers, including hepatocellular carcinoma (HCC). Additionally, LKB1 physically associates with p53 and regulates p53-dependent apoptotic pathways. To investigate whether genetic alterations of LKB1 could be involved in the tumorigenesis of HCC, we analysed the genetic alterations of the LKB1 and p53 genes in seven dysplastic nodules and 80 HCCs. We found one LKB1 missense mutation, CCG-->CTG (Pro-->Leu) at codon 281 within the kinase domain. We also found allelic loss in six of 27 (22%) informative HCC cases and all of them were HBV-positive cases. In addition, we detected seven missense, one nonsense and one silent mutations (nine of 80, 11%) of p53 in HCCs only. These results suggest that genetic alterations of the LKB1 or p53 genes may play an important role in tumour development or progression of a sub-set of HCCs, and may also provide alternative mechanisms to protect the HCC cell from p53-dependent apoptosis.
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PMID:Genetic analysis of the LKB1/STK11 gene in hepatocellular carcinomas. 1468 97

The LKB1 (also called serine/threonine kinase 11) tumor suppressor gene was cloned in 1998 by linkage analysis of Peutz-Jeghers cancer syndrome patients. Mammalian LKB1 has been implicated as a regulator of multiple biological processes and signaling pathways, including the control of cell-cycle arrest, p53-mediated apoptosis, Wnt signaling, transforming growth factor (TGF)-beta signaling, ras-induced cell transformation, and energy metabolism. The Caenorhabditis elegans and Drosophila melanogaster LKB1 homologs, termed PAR4 and dLKB1, respectively, regulate cell polarity. Recently, mammalian LKB1 was found to be active only in a complex with two other proteins--STRAD and MO25--and to induce complete polarization of intestinal epithelial cells in a cell-autonomous fashion. In this article, we summarize the findings regarding LKB1 over the past six years. In addition, we discuss LKB1 in polarity in the context of both the other PAR proteins and its tumor suppressive activities.
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PMID:LKB1 tumor suppressor protein: PARtaker in cell polarity. 1518 88

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 ATM protein kinase regulates the response of the cell to DNA damage by associating with and then phosphorylating proteins involved in cell cycle checkpoints and DNA repair. Here, we report on deletion studies designed to identify protein domains required for ATM to phosphorylate target proteins and to control cell survival following exposure to ionizing radiation. Deletion studies demonstrated that amino acids 1-150 of ATM were required for the ATM protein to regulate cellular radiosensitivity. Additional deletions and point mutations indicated that this domain extended from amino acids 81-106 of ATM, with amino acid substitutions located between amino acids 91 and 97 inactivating the functional activity of ATM. When ATM with mutations in this region (termed ATM90) was expressed in AT cells, it was unable to restore normal radiosensitivity to the cells. However, ATM90 retained normal kinase activity and was autophosphorylated on serine 1981 following exposure to DNA damage. Furthermore, wild-type ATM displayed DNA-damage induced association with p53, brca1, and LKB1 in vivo, whereas ATM90 failed to form productive complexes with these target proteins either in vivo or in vitro. Furthermore, ATM90 did not phosphorylate p53 in vivo and did not form nuclear foci in response to ionizing radiation. We propose that amino acids 91-97 of ATM contain a protein interaction domain required for the DNA damage-induced association between ATM and its target proteins, including the brca1, p53, and LKB1 proteins. Furthermore, this domain of ATM is required for ATM to form nuclear foci following exposure to ionizing radiation.
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PMID:DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminus of ATM. 1571 74

Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF- 1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high-penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low-penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.
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PMID:Understanding breast cancer risk -- where do we stand in 2005? 1578 78

Germline mutations in the LKB1 gene are responsible for Peutz-Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomas and increasing risk of cancer. Mice with Lkb1(+/-) mutation develop gastric hamartomas after >20 weeks of age, and hepatocellular adenomas and carcinomas >30 weeks. It has been reported that, in PJS patients, carcinomas progressed from hamartomas contain p53 mutations, and that LKB1 regulates p53-dependent apoptosis. To investigate the roles of LKB1 and p53 mutations in tumorigenesis, we constructed compound mutant mice of Lkb1 and p53 genes. In the Lkb1(+/-)p53(-/-) mice, formation of gastric hamartomas and hepatic tumors was accelerated. However, histopathology of hamartomas was similar between Lkb1(+/-)p53(-/-) and Lkb1(+/-) mice, and Lkb1 genotype remained heterozygous, suggesting that the p53 mutation affected hamartoma initiation. Contrary to the heterozygous hamartomas in the stomach and duodenum, the hepatic adenomas in Lkb1(+/-)p53(-/-) mice showed loss of Lkb1 heterozygosity (LOH), suggesting that lack of p53 stimulated Lkb1 LOH and tumor initiation in the liver. Taken together, these results indicate that lack of p53 causes earlier onsets of gastric hamartomas and hepatic tumors in Lkb1(+/-)p53(-/-) mice.
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PMID:Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice. 1627 73

Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1(+/-) and p53 null mice to generate Lkb1(+/-)/p53(+/-) and Lkb1(+/-)/p53(-/-) mice. Similar to the Lkb1(+/-) mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1(+/-)/p53(+/-) mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1(+/-)/p53(-/-) mice is approximately 2 months earlier than Lkb1(+/-)/p53(+/-) and Lkb1(+/-) mice, whereas the latter two show a similar time to onset which is at approximately 6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis.
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PMID:Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. 1635 36

The LKB1/STK11 serine/threonine kinase is mutated in Peutz-Jeghers syndrome and various sporadic cancers such as lung adenocarcinoma. We show here that LKB1 forms a complex with LMO4, GATA-6, and Ldb1, and enhances GATA-mediated transactivation in a kinase-dependent manner. We further demonstrate that LKB1 has the potential to induce p21 expression in collaboration with LMO4, GATA-6, and Ldb1 through the p53-independent mechanism. Our findings suggest that LKB1 regulates GATA-mediated gene expression and that this activity of LKB1 may be important for its tumor suppressor function.
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PMID:The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1. 1658 Jun 34


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