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)

Tumours derived from the thyroid follicular epithelium represent an informative model for understanding the molecular pathogenesis of multistage tumourigenesis, which is the prevailing theory on cancer development and progression nowadays. The early stages of thyroid tumour development appear to be the consequence of the activation or 'de novo' expression of several proto-oncogenes or growth factor receptors, such as ras, ret, NTRK, met, gsp and the thyrotropin (TSH) receptor. Alterations in the expression pattern of these genes are associated with the development of differentiated neoplasms, ranging from benign toxic adenomas (gsp and TSH receptor), to follicular (ras) and papillary (ret/PTC, NTRK, met) carcinomas. They may all be considered to be early events of thyroid cell transformation and, for some, experimental evidence derived from gene transfer studies supports this hypothesis. Alterations in tumour suppressor genes (p53, Rb) are associated instead with the most aggressive and poorly differentiated forms of thyroid cancer, indicating that, in the thyroid tumourigenic process, they represent late genetic events. Specific environmental factors (iodine deficiency, ionizing radiations) have been shown to play a crucial role in promoting the development of thyroid cancer, influencing both its genotypic and phenotypic features. Interestingly, a high percentage of genetic lesions causing thyroid cancer originate from gene rearrangements and chromosomal translocations (ret/PTC, NTRK, Pax-8/PPARgamma) a finding which, being a rare event in most epithelial tumours, makes the molecular pathogenesis of thyroid cancer unique. The uninterrupted flow of information on the molecular genetics of thyroid nodules and cancer will broaden the correlation between genotype and phenotype and will also provide important information for the development of more accurate preoperative diagnostic tools and more efficient treatment choices for the different forms of thyroid cancer.
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PMID:Molecular pathogenesis of thyroid nodules and cancer. 1128 33

APE/Ref-1 is a multifunctional protein possessing both redox and DNA repair functions. Through its redox activity, APE/Ref-1 controls the DNA-binding function of several transcriptional regulators (AP1, NF-kappaB, p53, Pax proteins). We have previously shown that APE/Ref-1 upregulates the transcriptional activity of the thyroid-specific transcription factor Pax8. In thyroid cells, APE/Ref-1 can be detected both in the nuclear and cytoplasmatic compartments. In this study regulatory mechanisms acting on APE/Ref-1 were revealed using the FRTL-5 cell line. TSH induces both cytoplasm-to-nucleus translocation and neosynthesis of APE/Ref-1 protein. Interestingly, only neosynthesis is dependent on cAMP signalling. In contrast, the cytoplasm-to-nucleus translocation is dependent on redox-mediated mechanisms. Based upon the data shown in this study and in others, a bimodal control of APE/Ref-1 by TSH can be delineated.
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PMID:APE/Ref-1 is controlled by both redox and cAMP-dependent mechanisms in rat thyroid cells. 1217 70

Despite multimodality treatment for thyroid cancer, including surgical resection, radioiodine therapy, thyrotropin (TSH)-suppressive thyroxine treatment, and chemotherapy/radiotherapy, survival rates have not improved over the last decades. Therefore, development and evaluation of novel treatment strategies, including gene therapy, are urgently needed. A variety of gene therapy approaches have been evaluated for the treatment of follicular cell-derived and medullary thyroid cancer, including corrective gene therapy (p53 restoration, expression of a dominant negative RET mutant), cytoreductive gene therapy (suicide gene/prodrug strategy herpes simplex virus-thymidine kinase [HSV-tk]/ganciclovir, antiangiogenic therapy with endostatin) and immunomodulatory gene therapy (expression of interleukin (IL)-2 and IL-12). Furthermore, cloning of the sodium iodide symporter (NIS) gene has paved the way for the development of a novel cytoreductive gene therapy strategy based on NIS gene transfer followed by the application of radioiodine therapy ((131)I). NIS gene delivery into medullary and follicular cell-derived thyroid cancer cells has been shown to be capable of establishing or restoring radioiodine accumulation and might therefore represent an effective therapy for medullary and dedifferentiated thyroid tumors that lack iodide accumulating activity. The data summarized in this review article clearly demonstrate that the currently available strategies represent potentially curative novel therapeutic approaches for future gene therapy of thyroid cancer. The combination of different therapeutic genes has been demonstrated to be very useful to enhance therapeutic efficacy and seems to have a promising role at least as part of a multimodality approach for advanced thyroid cancer.
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PMID:Gene therapy for thyroid cancer: current status and future prospects. 1524 69

We previously demonstrated that restoration of TP53 activity in anaplastic thyroid carcinoma inhibits cell growth and induces expression of thyroid differentiation markers. Here, we investigated whether TP53 status may condition the expression of therapeutic genes driven by retroviral LTR or tissue-specific enhancer elements. The TP53-defective ARO anaplastic thyroid carcinoma cells were transfected with TP53(Val135), which exhibits wild-type activity at 32 degrees C, and transduced with retroviral vectors, in which therapeutic genes were driven either by wild-type LTR or by a reshuffled LTR containing thyroglobulin (TG) enhancer. Both at 37 and 32 degrees C, expression of transgenes driven by TG enhancer was 10-fold lower than that obtained with wild-type LTR retroviral vector. TP53(Val135) transfer into ARO cells repressed transcription from wild-type LTR but increased expression of TG-driven therapeutic genes. This effect was markedly enhanced by cell culture at 32 degrees C and by TSH treatment. Cytotoxic effects shown after ganciclovir treatment paralleled therapeutic gene expression levels. In conclusion, TP53 status in the tumor cell can influence expression of therapeutic genes. When using retroviral-vector-based gene therapy, wild-type LTR vectors should be employed to target TP53-defective tumors, whereas thyroid-specific promoters should be used for transcriptional targeting of thyroid carcinomas carrying wild-type TP53.
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PMID:Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma. 1565 Jul 65

Tumour suppressor p53 is a transcription factor essential for DNA damage checkpoints during cellular response to stress. Mutations in the p53 gene are the most common genetic alterations found in human tumours; most pathogenetic modifications are missense mutations that abolish the p53 DNA-binding function. In the same cell type, distinct p53 missense mutations may determine different phenotypes. The PC Cl3 cell line retains several markers of thyroid differentiation in vitro. Introduction of the V143A mutant p53 allele, which abolishes the p53 DNA-binding function, leads to loss of differentiation markers as well as TSH dependency for growth. Conversely, PC Cl3 cells transfected with the S392A mutant p53 allele, presenting the mutation located outside the DNA-binding domain, show only loss of TSH dependency for growth. To identify molecular differences existing between PC Cl3 cell lines transformed by the V143A and the S392A mutant alleles, a differential proteomic approach was used. Two-dimensional gel electrophoresis analyses indicated that expression of a significant portion of protein species was modified by both p53 mutants. In fact, compared with wild-type PC Cl3 cells, modification of expression in V143A mutant cells occurred in 23.6% of the entire protein species. Conversely, modification of S392A mutant cells affected 14.0% of total proteins. Among these components, 8.3% were common to both mutants. Several of these proteins were identified by mass spectrometry procedures; some proteins, such as HSP90 and T-complex proteins, are already known to be related to p53 function.
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PMID:A differential proteomic approach to identify proteins associated with thyroid cell transformation. 1569 88

Pituitary apoplexy is an acute clinical event usually caused by hemorrhage or infarction in a pituitary adenoma. We report the unusual case of hemorrhagic pituitary apoplexy in an 18 year-old male with previously undiagnosed type 2 diabetes mellitus who presented with unexplained hyperglycemia (glucose 49.2 mmol/l [887 mg/dl]) and obtundation and in whom an initial diagnosis of non-ketotic hyperglycemic coma (NKHC) was made. MRI revealed a heterogeneous mass arising from an expanded sella turcica into the suprasellar cistern. Despite well-controlled glucose levels on continuous insulin infusion, dexamethasone, and initiation of bromoergocriptine (parlodel) therapy, the patient's vision and pupillary responses deteriorated acutely. Following emergency transphenoidal surgery, the patient's vision and mental status improved. Data confirmed preoperative panhypopituitarism; serum prolactin was 396 ng/ml (microg/l). Immunostudies demonstrated tumoral labeling for prolactin, but not for ACTH, GH, TSH, LH, FSH, or P53.
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PMID:Hemorrhagic pituitary apoplexy in an 18 year-old male presenting as non-ketotic hyperglycemic coma (NKHC). 1604 31

We report the characteristics of three cell lines (designated, SNU-80, SNU-373 and SNU-790), which were established from two papillary carcinomas and one anaplastic carcinoma obtained from three Korean thyroid carcinoma patients. All cell lines grow as adherent cells. Electron microscopy characteristically showed cytoplasmic invaginations of nuclei and intranuclear cytoplasmic inclusions. SNU-80 and SNU-790 cells showed a positive reaction to anti-cytokeratin antibody, and SNU-790 cells positivity for CK-19. All lines were free of mycoplasma or bacteria and were proven unique by DNA fingerprinting analysis. The p15 and p16 genes are deleted in the SNU-790 line. Mutations of the p53 gene were found in two lines (SNU-80 and SNU-373), but no mutations in the RET or MEN1 genes were observed. Mutations of the BRAF gene were found in the SNU-80 (G468R) and the SNU-790 (V599E) cell lines, but no mutations in the K-ras gene were present. SNU-80 and SNU-790 cells showed a positive reaction to anti-cytokeratin antibody, and no evidence of the production of thyroglobulin or calcitonin was observed. The cell lines were unable to trap radioactive iodine but did not contain TSH receptor. In addition, we investigated the mRNA expression levels of Tg, TSHR, TTF-1, PAX-8, NIS, IL-6, and LIF, and of the alpha, beta and gamma retinoic acid receptors in these cell lines. IL-6 was down-regulated in all three cell lines by all-trans-retinoic acid treatment. RAR-alpha was expressed but RAR-beta was not expressed in the three cell lines, and RAR-gamma was not expressed in SNU-790. Interestingly, RAR-beta (SNU-80 and SNU-373) and RAR-gamma (SNU-790) was up-regulated by all-trans-retinoic acid treatment. We believe that these well-characterized thyroid carcinoma cell lines may be useful tools for investigations on the biological characteristics of thyroid carcinoma, particularly for investigations related to gene alterations, especially of the BRAF gene. These cell lines may also be useful for redifferentiation therapy studies on thyroid carcinoma using all-trans-retinoic acid.
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PMID:Establishment and characterization of cell lines from three human thyroid carcinomas: responses to all-trans-retinoic acid and mutations in the BRAF gene. 1713 24

Cancer is a multistep phenomenon and multiple genetic lesions are involved in the emergence of the cancerous lesion. This has best been demonstrated in colonic cancer. The authors review their work and that of others highlighting what is known about thyroid cancer. They implicate ras mutations predominantly in follicular carcinoma, rearrangement of the ret proto-oncogene in papillary carcinoma and the tumor suppressor genes p53 and retinoblastoma gene product in all stages of thyroid carcinoma. They find a low rate of ret proto-oncogene rearrangement in the Saudi population (>5%) as compared to elsewhere in the world (20%). They find TSH receptor message abundance to be predictive of prognosis in thyroid cancer patients. Lastly, they examine whether the abundance of the anti-metastatic gene nm23 message abundance negatively correlated with the tendency of thyroid tumors to metastasize and find that not to be the case in thyroid carcinoma. The study of oncogenes and tumor suppressor genes in the pathogenesis of thyroid cancer is in its infancy; however, rapid progress is being made in identifying genes participating in malignant thyroid cell transformation.
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PMID:Towards understanding the molecular basis of thyroid cancer. 1759 May 79

The objective of this study was to describe a familial screening for AIP mutations in the context of aggressive prolactinoma in childhood. A 12-year-old boy, presented headaches and bilateral hemianopsia. He had adequate height and weight for his age (50(th) percentile), Tanner stage G1 P1. His bone age was 10 years. Prolactin was 10.560 ng/mL (3-25), FSH and LH were undetectable, IGF-1, TSH, Free T4, ACTH, and cortisol were within normal ranges. MRI showed a pituitary macroadenoma, 5.3 X 4.0 X 3.5 cm with compression of the optic chiasm, bilateral cavernous sinus invasion, encasement of carotids, and extension to clivus. Surgical debulking was performed. Resistance to cabergoline was characterized and he was submitted to two surgeries and radiotherapy. Immunohistochemical evaluation included prolactin, ACTH, GH, FSH, LH,AIP, c-erb B2, Ki-67, and p53. Genomic DNA was isolated from the index case and 48 relatives, PCR and sequencing were performed.A germline A195V mutation in AIP was identified in the index case and in five asymptomatic relatives. Germline mutations in the AIP gene may be involved in the predisposition to pituitary adenoma formation, as cause or co-factor in pathogenesis of aggressive tumors in young patients.
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PMID:Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene. 2134 Jan 66

Malignant tumours specific for the thyroid gland originate from either the follicular cells (papillary, follicular undifferentiated carcinomas) or the parafollicular C-cell system (medullary carcinomas). Regarding the follicle derived carcinomas, various types of data indicate that radiation exposure, for example therapeutic radiation given to children for benign disorders in the head and neck area, is an important risk factor. Dietary components may also be relevant. The marked female predominance. which is not specific for malignant tumours, is probably the result of hormonal cofactors and differences in growth promotion of early lesions (microcarcinomas). Further development of follicle derived tumours is characterized by decreasing tumour cell dependence of TSH, along with the introduction of autocrine loops, e.g. expression of the TGF alpha/EGF-receptor system. and such mechanisms may in part explain the development of autonomous growth. In parallel with these phenotypic changes, several alterations have also been described in various thyroid tumours, including the medullary carcinomas, for example in the ras and ret genes. Activation of some oncogenes, like the EGF-receptor system, may also be relevant for late tumor progression and hence of prognostic value. to-ether with other factors like p53 and nm23. In addition to classical clinocopathological features, molecular data are of increasing importance in biological grading of thyroid tumours.
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PMID:Thyroid-cancer - some aspects of epidemiology and etiologic factors, pathological features and tumor biology. 2156 3


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