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- Forsberg, L, et al.
(author)
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Homozygous inactivation of the MEN1 gene as a specific somatic event in a case of secondary hyperparathyroidism
- 2001
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In: European journal of endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 145:4, s. 415-420
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Journal article (peer-reviewed)abstract
- BACKGROUND: Most patients who have been surgically treated for secondary hyperparathyroidism (HPT) harbor at least one pathological parathyroid gland with a tumor of monoclonal origin. OBJECTIVE: To elucidate the underlying genetic mechanisms behind secondary HPT, by studying a panel of such tumors for numerical alterations. METHODS: Sixteen parathyroid glands from eight patients (median age 58 years, range 31-74 years), were screened for numerical chromosomal imbalances, using comparative genomic hybridization (CGH). Mutation analysis of the multiple endocrine neoplasia type 1 gene (MEN1) was also performed by sequencing of the coding region. RESULTS: The results show that gross chromosomal alterations occur rarely in secondary HPT. In one of the three glands analyzed from one patient, a complete loss of chromosome 11 was detected. This gland also had an inactivating nonsense mutation, E469X, of the MEN1 gene. The mutation was present neither in the other two glands, nor in the constitutional tissue of the same patient, thus confirming its somatic origin. CONCLUSIONS: The relative lack of numerical chromosomal alterations would suggest that more discrete genetic alterations are responsible for the monoclonal growth in the majority of cases of secondary HPT. Furthermore, somatic inactivation of the MEN1 tumor suppressor gene contributes to the tumorigenesis in a small proportion of the cases.
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- Mahmoudi, S, et al.
(author)
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WRAP53 promotes cancer cell survival and is a potential target for cancer therapy
- 2011
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In: CELL DEATH and DISEASE. - : Nature Publishing Group. - 2041-4889. ; 2:e114
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Journal article (peer-reviewed)abstract
- We previously identified WRAP53 as an antisense transcript that regulates the p53 tumor suppressor. The WRAP53 gene also encodes a protein essential for Cajal body formation and involved in cellular trafficking of the survival of motor neuron complex, the telomerase enzyme and small Cajal body-specific RNAs to Cajal bodies. Here, we show that the WRAP53 protein is overexpressed in a variety of cancer cell lines of different origin and that WRAP53 overexpression promotes cellular transformation. Knockdown of the WRAP53 protein triggers massive apoptosis through the mitochondrial pathway, as demonstrated by Bax/Bak activation, loss of mitochondrial membrane potential and cytochrome c release. The apoptosis induced by WRAP53 knockdown could moreover be blocked by Bcl-2 overexpression. Interestingly, human tumor cells are more sensitive to WRAP53 depletion as compared with normal human cells indicating that cancer cells in particular depends on WRAP53 expression for their survival. In agreement with this, we found that high levels of WRAP53 correlate with poor prognosis of head and neck cancer. Together these observations propose a role of WRAP53 in carcinogenesis and identify WRAP53 as a novel molecular target for a large fraction of malignancies.
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