Mutational abrogation of the gene in gastrointestinal polyps in patients with Cowden disease

Chi, Sung–Gil; Kim, Hyo‐Jong; Park, Bum-Joon; Min, Hyun-Jung; Park, Jaehoon; Kim, Youn-Wha; Dong, Seok‐Ho; Kim, Byung-Ho; Lee, Jung-Il; Chang, Young Eun; Chang, Rin; Kim, Woo-Kap; Yang, Moon Ho

doi:10.1016/s0016-5085(98)70078-2

Cited by 44 publications

(36 citation statements)

References 16 publications

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“…Familial occurrence has been observed and it is thought to be a multisystem disease complex inherited in an autosomal dominant manner ( 1 ). Recently, it was reported that the mutational abrogation of the tumor suppressor gene, namely, phosphatase and tensin homolog deleted on chromosometen/ mutated in multiple advanced cancers (PTEN/MMAC 1 ) plays a causal role in the genesis of gastrointestinal polyps in Cowden's disease (32). Wefound these mutations of the PTEN gene on 10 q in the present case and the details will be reported along with another case.…”

Section: Discussionsupporting

confidence: 54%

Cowden's Disease Diagnosed through Mucocutaneous Lesions and Gastrointestinal Polyposis with Recurrent Hematochezia, Unrevealed by Initial Diagnosis.

et al. 2000

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A 51-year-old man was admitted to our hospital because of hematochezia and painful keratotic plaques involving both hands. He had gastrointestinal polyposis, and a history of liver hemangiomas and thyroid tumor. Numerous papules on the face and papillomatosis on the oral mucosa were present. A diagnosis was madeas a typical case of Cowden's disease according to the criteria proposed by Salem and Steck (J AmAcad Dermatol 8: 686, 1983). The patient was not correctly diagnosed initially in spite of typical manifestations of Cowden's disease, mainly due to his concomitant manifestations which occurred chronologically.

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Section: Discussionsupporting

confidence: 54%

Cowden's Disease Diagnosed through Mucocutaneous Lesions and Gastrointestinal Polyposis with Recurrent Hematochezia, Unrevealed by Initial Diagnosis.

et al. 2000

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“…Extraction of total cellular RNA and synthesis of cDNA were performed as previously described. 19 Genomic DNA was extracted from the same cells of the tissues from the DNA phase after RNA was extracted.…”

Section: Gastric Tissues Cell Lines and Treatmentmentioning

confidence: 99%

“…The PCR reaction was initially performed over a range of cycles (24,27,30,33, 36 and 40 cycles) and 2 l of 1:4 diluted cDNA (12.5 ng/50 l PCR reaction) undergoing 30 -36 cycles was observed to be within the logarithmic phase of amplification with primer sets R2-5/R2-6 (270 bp) and R2-1/R2-7 (270 bp) for p53R2 and G3/G4 (587 bp) for GAPDH used as an endogenous expression standard. 19 The sequences of primers used for PCR analysis of p53R2 are described in Table I. In every (RT-PCR) assay, blank cDNA (without reverse transcriptase) and blank PCR (without cDNA) were included as negative controls.…”

Section: Semi-quantitative Rt-and Genomic Pcr Analysesmentioning

confidence: 99%

Expression and mutation analyses of P53R2, a newly identified p53 target for DNA repair in human gastric carcinoma

Byun

Chae

Ryu

et al. 2002

Intl Journal of Cancer

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p53R2, a recently identified putative tumor suppressor located at 8q23.1, encodes a protein with striking similarity to a small subunit of ribonucleotide reductase. p53R2 is directly induced by wild-type p53 and involved in the p53 checkpoint for repair of damaged DNA, raising the possibility that mutational inactivation of p53R2 may contribute to the development and progression of human malignancies. To explore the p53R2's candidacy for a suppressor in gastric tumorigenesis, we examined the expression and mutation status of p53R2 in 166 gastric specimens including 90 primary adenocarcinomas and 15 cell lines. In response to genotoxic damages, p53R2 transcription was clearly activated in wild-type but not mutant-type p53-carrying cells while basal expression of p53R2 in undamaged cells showed no association with the mutational status of p53. Host cell reactivation assay revealed that p53R2 enhances DNA repair efficiency and plays a role in the p53-mediated repair of damaged DNA, whereas no significant effect of p53R2 on cell growth and apoptosis was detected in flow cytometry and [ 3 H]thymidine incorporation assays. p53R2 transcript was expressed in all normal and tumor tissues and its expression levels were not significantly different between normal and malignant carcinoma tissues. p53R2 expression showed no correlation with stage, grade and histological types of tumors. Moreover, no tumorspecific reduction of p53R2 was detected in 30 matched sets. Mutational analysis of p53R2 in 105 carcinomas including 15 cell lines also failed to detect any evidences for genomic deletion or somatic mutations leading to amino acid substitutions or frameshift whereas 31% (28 of 90) of the same primary tumors showed p53 alterations. Whereas 82% (23 of 28) of the mutant p53-carrying primary tumors expressed abnormally low p21Waf1 , no association of p53R2 expression with the p53 status was recognized, suggesting that basal transcription of p53R2 is regulated through the p53-independent mechanism. Collectively, our study indicates that although p53R2 is induced in a p53-dependent manner and involved the p53-mediated DNA repair in gastric epithelial cells, it is not a critical target of genetic inactivation in gastric tumorigenesis.

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“…To provide an example of this, we investigated mutations that have previously been shown to ablate major mono-ubiquitination sites in PTEN. K13 in PTEN is mutated to glutamic acid (K13E) in spontaneous cancer 45 and K289 mutated to glutamic acid (K289E) is associated with Cowden syndrome 46,47 . These sites are found on unstructured regions of PTEN 14 ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure-function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G proteincoupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.

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Mutational abrogation of the gene in gastrointestinal polyps in patients with Cowden disease

Cited by 44 publications

References 16 publications

Cowden's Disease Diagnosed through Mucocutaneous Lesions and Gastrointestinal Polyposis with Recurrent Hematochezia, Unrevealed by Initial Diagnosis.

Cowden's Disease Diagnosed through Mucocutaneous Lesions and Gastrointestinal Polyposis with Recurrent Hematochezia, Unrevealed by Initial Diagnosis.

Expression and mutation analyses of P53R2, a newly identified p53 target for DNA repair in human gastric carcinoma

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

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