共查询到20条相似文献,搜索用时 31 毫秒
1.
Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Isakoff MS Sansam CG Tamayo P Subramanian A Evans JA Fillmore CM Wang X Biegel JA Pomeroy SL Mesirov JP Roberts CW 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(49):17745-17750
2.
Previous studies indicated that region 11.2 of the long arm of chromosome 22 (22q11.2) might be a locus encoding a tumor suppressor
gene, since its deletion is a recurrent genetic characteristic of aggressive pediatric cancer. This region is found in the
human immunodeficiency virus integrase interactor 1 (hSNF5/INI1) gene. To investigate whether the hSNF5/INI1 gene is involved
in leukemogenesis, mutation analysis of the hSNF5/INI1 gene was performed in the present study using 5 hematopoietic cell
lines, acute myeloid leukemia (AML) specimen and normal control. We found two single nucleotide polymorphisms at the hSNF5/INI1
gene in exon 4 and exon 9. The results of this study suggest that the hSNF5/INI1 gene does not play an important role in the
leukemogenesis of AML. 相似文献
3.
Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten 总被引:8,自引:0,他引:8
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Backman SA Ghazarian D So K Sanchez O Wagner KU Hennighausen L Suzuki A Tsao MS Chapman WB Stambolic V Mak TW 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(6):1725-1730
PTEN is a tumor suppressor gene mutated in various advanced human neoplasias, including glioblastomas and prostate, breast, endometrial, and kidney cancers. This tumor suppressor is a lipid phosphatase that negatively regulates cell survival and proliferation mediated by phosphatidylinositol 3-kinase/protein kinase B signaling. Using the Cre-loxP system, we selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer. These data demonstrate that Pten is an important physiological regulator of growth in the skin and prostate. Further, the early onset of HGPIN in Pten mutant males is unique to this animal model and implicates PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicate that PTEN is a critical tumor suppressor in this organ. 相似文献
4.
Benzo[a]pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. 总被引:11,自引:0,他引:11
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
B Ruggeri M DiRado S Y Zhang B Bauer T Goodrow A J Klein-Szanto 《Proceedings of the National Academy of Sciences of the United States of America》1993,90(3):1013-1017
Human tobacco-related cancers exhibit a high frequency of G to T transversions in the mutation hot spot region of the p53 tumor suppressor gene, possibly the result of specific mutagens in tobacco smoke, most notably benzo[a]pyrene (B[a]P). No in vivo animal model of B[a]P-induced tumorigenesis has been used, however, to substantiate these molecular epidemiological data experimentally. Direct DNA sequence analysis of the hot spot region (exons 5-8 inclusive) of murine p53 was performed in 20 skin tumors induced by a complete carcinogenesis protocol with B[a]P. Sequence analyses revealed numerous heterozygous missense mutations in carcinomas, specifically in exons 7 and 8 of the p53 gene, and targeting exclusively guanine residues. Moreover, 70% (5/7) of the mutations characterized were G to T transversions. In contrast, direct DNA sequence analysis of 36 skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in either a complete carcinogenesis protocol or in a two-stage carcinogenesis protocol revealed a 30% frequency of heterozygous p53 mutations, with the majority of mutations found in carcinomas, but only a single G to T transversion (1/8). Thus, while mutation frequencies are similar, the pattern and type of p53 mutations in B[a]P-induced skin tumors differs significantly from the mutation spectra in DMBA-induced squamous neoplasias. These in vivo findings in B[a]P-induced tumors lend support to in vitro and molecular epidemiological evidence, suggesting that the p53 tumor suppressor gene may be a selective target of metabolically activated B[a]P species etiologically associated with human tobacco-related cancers. 相似文献
5.
Tara L. Roberts Uda Ho John Luff C. Soon Lee Simon H. Apte Kelli P. A. MacDonald Liza J. Raggat Allison R. Pettit Carl A. Morrow Michael J. Waters Phil Chen Rick G. Woods Gethin P. Thomas Liam St. Pierre Camile S. Farah Raymond A. Clarke James A. L. Brown Martin F. Lavin 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(4):E285
SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense-mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development. 相似文献
6.
Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch 总被引:1,自引:0,他引:1
Shih HP Gross MK Kioussi C 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(14):5907-5912
Pitx2 expression is observed during all states of the myogenic progression in embryonic muscle anlagen and persists in adult muscle. Pitx2 mutant mice form all but a few muscle anlagen. Loss or degeneration in muscle anlagen could generally be attributed to the loss of a muscle attachment site induced by some other aspect of the Pitx2 phenotype. Muscles derived from the first branchial arch were absent, whereas muscles derived from the second branchial arch were merely distorted in Pitx2 mutants at midgestation. Pitx2 was expressed well before, and was required for, initiation of the myogenic progression in the first, but not second, branchial arch mesoderm. Pitx2 was also required for expression of premyoblast specification markers Tbx1, Tcf21, and Msc in the first, but not second, branchial arch. First, but not second, arch mesoderm of Pitx2 mutants failed to enlarge after embryonic day 9.5, well before the onset of the myogenic progression. Thus, Pitx2 contributes to specification of first, but not second, arch mesoderm. The jaw of Pitx2 mutants was vestigial by midgestation, but significant size reductions were observed as early as embryonic day 10.5. The diminutive first branchial arch of mutants could not be explained by loss of mesoderm alone, suggesting that Pitx2 contributes to the earliest specification of jaw itself. 相似文献
7.
Mutations of the p53 gene in malignant rhabdoid tumors of soft tissue and the kidney: immunohistochemical and DNA direct sequencing analysis 总被引:1,自引:0,他引:1
Yoshiaki Kinoshita Hideki Shiratsuchi Sadafumi Tamiya Yumi Oshiro Yoichi Hachitanda Yoshinao Oda Sachiyo Suita Masazumi Tsuneyoshi 《Journal of cancer research and clinical oncology》2001,127(6):351-358
Malignant rhabdoid tumor (MRT) is characterized by the presence of intracytoplasmic eosinophilic inclusions composed of whorls
of intermediate filaments. This tumor was originally described as an entity of the abortive type of Wilms' tumor in childhood.
Recently, it has been proved that these rhabdoid cells can be observed in various types of malignant tumors, including soft
tissue sarcoma or carcinoma. To investigate the oncogenesis of this tumor, we examined the p53 gene alteration by means of
immunohistochemical analysis and DNA direct sequencing in three cases of malignant rhabdoid tumor (MRT) of the soft tissue
and three cases of MRT of the kidney. All the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed
immunopositivity for p53 protein. Among them, one of the cases of MRT of the soft tissue and two of the cases of MRT of the
kidney showed missense mutations of the p53 gene. These results strongly suggest that p53 gene alterations may have an important
role to play in the aggressive biological behavior and poor prognosis of this tumor.
Received: 7 June 2000 / Accepted: 10 October 2000 相似文献
8.
Kucherlapati M Yang K Kuraguchi M Zhao J Lia M Heyer J Kane MF Fan K Russell R Brown AM Kneitz B Edelmann W Kolodner RD Lipkin M Kucherlapati R 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(15):9924-9929
Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer. 相似文献
9.
Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nagai M Tanaka S Tsuda M Endo S Kato H Sonobe H Minami A Hiraga H Nishihara H Sawa H Nagashima K 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(7):3843-3848
10.
Nathan P. Young Tyler Jacks 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(22):10184-10189
The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-rasG12D in vivo has not been examined. Using compound mutant mice containing the ArfGFP reporter and the spontaneously activating K-rasLA2 allele, we have uncovered dramatic tissue specificity of K-rasG12D-dependent p19Arf up-regulation. Lung tumors, which can arise in the presence of functional p19Arf, rarely display p19Arf induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19Arf-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19Arf induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation. 相似文献
11.
Keyes WM Vogel H Koster MI Guo X Qi Y Petherbridge KM Roop DR Bradley A Mills AA 《Proceedings of the National Academy of Sciences of the United States of America》2006,103(22):8435-8440
Homology between p63 and p53 has suggested that these proteins might function similarly. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63+/- mice in both WT and p53-compromised backgrounds. We found that p63+/- mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53+/- mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53+/- mice. Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53. 相似文献
12.
Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. 总被引:8,自引:1,他引:8
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
M M Matzuk M J Finegold J P Mather L Krummen H Lu A Bradley 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(19):8817-8821
Activins and inhibins, members of the type beta transforming growth factor superfamily of growth regulatory proteins, are produced in multiple tissues and affect diverse physiologic processes. Using embryonic stem cell technology, we previously demonstrated that inhibin can function as a gonadal tumor suppressor. In this study, we show that development of gonadal tumors is rapidly followed by a cancer cachexia-like wasting syndrome. Cachectic inhibin-deficient mice develop hepatocellular necrosis around the central vein and parietal cell depletion and mucosal atrophy in the glandular stomach, are anemic, and demonstrate severe weight loss. The liver pathology is consistent with studies demonstrating an effect of elevated activins on rat hepatocytes. In inhibin-deficient mice with tumors, activins are > 10-fold elevated in the serum and are likely causing some of the cachexia symptoms. In contrast, inhibin-deficient mice gonadectomized at an early age do not develop this wasting syndrome. However, these gonadectomized, inhibin-deficient mice eventually develop adrenal cortical sex steroidogenic tumors with nearly 100% penetrance, demonstrating that inhibin is also a tumor suppressor for the adrenal gland. 相似文献
13.
A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors 总被引:15,自引:0,他引:15
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Crabtree JS Scacheri PC Ward JM Garrett-Beal L Emmert-Buck MR Edgemon KA Lorang D Libutti SK Chandrasekharappa SC Marx SJ Spiegel AM Collins FS 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(3):1118-1123
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene. 相似文献
14.
Cecilia Sgadari AnneL. Angiolillo BarryW. Cherney SandraE. Pike JoshuaM. Farber LeonidasG. Koniaris Padmavathy Vanguri ParrisR. Burd Nasreen Sheikh Ghanshyam Gupta Julie Teruya-Feldstein Giovanna Tosato 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(24):13791-13796
Human Burkitt lymphoma cell lines give rise to progressively growing subcutaneous tumors in athymic mice. These tumors are induced to regress by inoculation of Epstein–Barr virus-immortalized normal human lymphocytes. In the present study, analysis of profiles of murine cytokine/chemokine gene expression in Burkitt tumor tissues excised from the nude mice showed that expression of the murine α-chemokine interferon-inducible protein-10 (IP-10) was higher in the regressing than in the progressive Burkitt tumors. We tested the effects of IP-10 on Burkitt tumor growth in nude mice. Inoculation of established Burkitt tumors either with crude preparations of murine IP-10 or with purified human IP-10 caused visible tumor necrosis in a proportion of the animals, although no complete tumor regressions were observed. Constitutive expression of murine IP-10 in Burkitt cells reduced their ability to grow as subcutaneous tumors, and caused visible tumor necrosis in a proportion of the animals. Histologically, IP-10-treated and IP-10-expressing Burkitt tumors had widespread evidence of tumor tissue necrosis and of capillary damage, including intimal thickening and vascular thrombosis. Thus, IP-10 is an antitumor agent that promotes damage in established tumor vasculature and causes tissue necrosis in human Burkitt lymphomas established subcutaneously in athymic mice. 相似文献
15.
Cervantes RB Stringer JR Shao C Tischfield JA Stambrook PJ 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(6):3586-3590
Pluripotent embryonic stem (ES) cells have been used to produce genetically modified mice as experimental models of human genetic diseases. Increasingly, human ES cells are being considered for their potential in the treatment of injury and disease. Here we have shown that mutation in murine ES cells, heterozygous at the selectable Aprt locus, differs from that in embryonic somatic cells. The mutation frequency in ES cells is significantly lower than that in mouse embryonic fibroblasts, which is similar to that in adult cells in vivo. The distribution of spontaneous mutagenic events is remarkably different between the two cell types. Although loss of the functional allele is the predominant mutation type in both cases, representing about 80% of all events, mitotic recombination accounted for all loss of heterozygosity events detected in somatic cells. In contrast, mitotic recombination in ES cells appeared to be suppressed and chromosome loss/reduplication, leading to uniparental disomy (UPD), represented more than half of the loss of heterozygosity events. Extended culture of ES cells led to accumulation of cells with adenine phosphoribosyltransferase deficiency and UPD. Because UPD leads to reduction to homozygosity at multiple recessive disease loci, including tumor suppressor loci, in the affected chromosome, the increased risk of tumor formation after stem cell therapy should be viewed with concern. 相似文献
16.
17.
Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. 总被引:16,自引:4,他引:16
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
O Hino A J Klein-Szanto J J Freed J R Testa D Q Brown M Vilensky R S Yeung K D Tartof A G Knudson 《Proceedings of the National Academy of Sciences of the United States of America》1993,90(1):327-331
Hereditary renal carcinoma (RC) in the rat, originally reported by R. Eker in 1954, is an example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. At the histologic level, RCs develop through multiple stages from early preneoplastic lesions (e.g., atypical tubules) to adenomas in virtually all heterozygotes by the age of 1 year. The homozygous mutant condition is lethal at approximately 10 days of fetal life. Ionizing radiation induces additional tumors in a linear dose-response relationship, suggesting that in heterozygotes two events (one inherited, one somatic) are necessary to produce tumors, and that the predisposing gene is a tumor suppressor gene. No genetic linkage has yet been found between the Eker mutation and rat DNA sequences homologous to those in human chromosome 3p, the presumed site of the putative tumor suppressor gene responsible for human RC. Nonrandom loss of rat chromosome 5 in RC-derived cell lines is sometimes associated with homozygous deletion of the interferon gene loci at rat chromosome bands 5q31-q33. Since this locus is not linked with the predisposing inherited gene in the Eker rat, it probably represents a second tumor suppressor gene involved in tumor progression. 相似文献
18.
A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer 总被引:17,自引:0,他引:17
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Kim S Chin K Gray JW Bishop JM 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(46):16251-16256
19.
Foukakis T Au AY Wallin G Geli J Forsberg L Clifton-Bligh R Robinson BG Lui WO Zedenius J Larsson C 《The Journal of clinical endocrinology and metabolism》2006,91(3):1143-1149
CONTEXT: The Ras effector NORE1A (RASSF5A) is a putative tumor suppressor and is inactivated in several human cancers. NORE1A has not been studied in thyroid cancer. OBJECTIVE: The objective of this study was to investigate whether NORE1A is involved in follicular thyroid cancer (FTC) development. DESIGN: We analyzed NORE1A expression in 25 FTCs, eight follicular thyroid adenomas, and seven normal thyroid tissues by TaqMan quantitative RT-PCR. The results were evaluated in relation to RASSF1A expression, RAS mutations, and PAX8-PPARgamma fusions assessed in the same material. NORE1A promoter methylation was assessed by the combined bisulfite restriction endonuclease assay. RESULTS: Although the NORE1A mRNA levels of the majority of the tumors were similar to those in the normal controls, the cases harboring a PAX8-PPARgamma translocation (n = 6) exhibited dramatically reduced NORE1A expression (P < 0.001). In contrast, RAS mutations (n = 5) and NORE1A down-regulation were mutually exclusive. A significant reduction in the expression of the NORE1A homolog and the bona fide tumor suppressor gene RASSF1A was observed, but with weak correlation to the respective NORE1A values. No NORE1A promoter methylation was detected in the 32 thyroid tumors analyzed. CONCLUSIONS: Our experiments demonstrate the suppression of NORE1A, a known Ras effector, in PAX8-PPARgamma carrying FTCs. 相似文献
20.
Rabbit V2 carcinoma tissues have been described to possess a procoagulant activity with specific characteristics; this material has been purified and identified as a cysteine proteinase able to directly activate coagulation factor X. We have shown here that the procoagulant activity of V2 carcinoma extracts is depressed in warfarin-treated animals, thus suggesting that cancer procoagulant could represent a new vitamin K-dependent protein. The biochemical basis for this effect is offered by the identification of gamma-glutamyl carboxylase in the microsomal fraction of tumor tissues. The V2 carcinoma has a carboxylase activity which is increased in warfarin-treated animals. An endogenous substrate of tumor carboxylase, the nature of which has not been identified, has been found 5-fold increased in warfarin-treated animals. The presence of gamma-glutamyl carboxylase was also described in several murine tumors including both carcinomas and fibrosarcomas. It is worth mentioning that all the tumors tested produce a procoagulant with the peculiar characteristics of that described in V2 carcinoma. It is conceivable that cancer procoagulant could represent at least one of the substrates for gamma-glutamyl carboxylase in these experimental tumor tissues. 相似文献