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

Although thyroid cancer tends to metastasize early in children, it is generally associated with a good prognosis. In this study, the expression of p53, mutations of which are found in many cancers, including anaplastic thyroid cancer, was examined to determine the relationship between cell proliferation and the clinical course of thyroid cancer. The clinicopathological findings and clinical courses of 15 children who underwent surgery before the age of 18 years at our hospital between 1972 and 1992 were examined, and the expression of p53 was studied using immunohistochemical techniques and an RNase protection assay. Postoperative follow-up ranged from 1 to 20 years, with a median of 12 years. No abnormal expression of p53 was detected in the thyroid cancer of any of the children tested, and none of them have died. The findings of this study therefore strongly suggest that p53 may play a role in the regulation of cell proliferation, and in this capacity slow the growth of and be related to the prognosis of differentiated thyroid cancer in children.
 ...
PMID:Clinicopathological findings and p53 expression of thyroid cancer in children. 764 Apr 49

The development and progression of thyroid tumors is signaled by phenotype-specific mutations of genes involved in growth control. Molecular events associated with undifferentiated thyroid cancer are not known. We examined normal, benign, and malignant thyroid tissue for structural abnormalities of the p53 tumor suppressor gene. Mutations were detected by single-strand conformation polymorphisms of PCR-amplified DNA, using primers bracketing the known hot spots on either exons 5, 6, 7, or 8. The prevalence of mutations was as follows: normal thyroid 0/6; follicular adenomas 0/31; papillary carcinomas 0/37; medullary carcinomas 0/2; follicular carcinomas 1/11; anaplastic carcinomas 5/6; thyroid carcinoma cell lines 3/4. Positive cases were confirmed by direct sequencing of the PCR products. All five anaplastic carcinoma tissues and the anaplastic carcinoma cell line ARO had G:C to A:T transitions leading to an Arg to His substitution at codon 273. In both tumors and cell lines, examples of heterozygous and homozygous p53 mutations were identified. The only thyroid carcinoma cell line in which p53 mutations were not detected in exons 5-8 had markedly decreased p53 mRNA levels, suggesting the presence of a structural abnormality of either p53 itself or of some factor controlling its expression. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggests that inactivation of p53 may confer these neoplasms with aggressive properties, and further loss of differentiated function.
 ...
PMID:High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. 842 16

Anaplastic thyroid carcinoma (ATC) is usually associated with a poor prognosis, with most patients dying within a few months. The mechanism of its carcinogenesis is unclear, and its rapid growth and spread often prevent effective surgical therapy. Thus, chemotherapy is necessary. However, ATC is often resistant to anticancer drugs. Therefore, prediction of chemosensitivity is important in selecting appropriate treatment. In this study, after the establishment of three cell lines (K119, KOA2, and IAA) from patients with ATC, we analyzed them for abnormalities in certain oncogenes (myc, ras, ret, and c-erbB2) and the p53 tumor suppressor gene. Only one of three cell lines (KOA2) had a N-ras mutation [codon 61 CAA(Gln)-->CGA(Arg)] and a p53 gene mutation [exon 6 codon 192 Caa(Gln)-->TAG(stop)]. We also investigated their in vitro drug sensitivity and compared it with clinical chemosensitivity, retrospectively. In vitro drug sensitivity was determined using an adhesive tumor cell culture system. Only the K119 cells were sensitive to adriamycin and cisplatin in vitro. The other two were resistant to them in vitro. These results paralleled the clinical responses. We also evaluated the in vitro drug sensitivity of a poorly differentiated thyroid carcinoma cell line (SMP) and papillary thyroid carcinoma cell lines (NPA). None of the five cell lines expressed the multidrug resistance gene (mdr-1). In conclusion, we established ATC cell lines that are suitable models for characterizing the nature of multidrug resistance and carcinogenesis.
 ...
PMID:Establishment of anaplastic thyroid carcinoma cell lines useful for analysis of chemosensitivity and carcinogenesis. 885 99

We investigated the p53 status and the ability of exogenous wildtype (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulation of p53 or induction of p21WAF1/CIP1 or Mdm-2 and did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had mutant p53. SW-1736 cells were functionally mutant because of marked down-regulation of wt p53 messenger ribonucleic acid, representing a novel mechanism of p53 dysfunction. Infection with a p53-expressing adenovirus (Ad-p53) induced high levels of p21 and Mdm-2 proteins. In BHT-101 cells, induction of p21 and Mdm-2 was evident 10 h after infection. In KAT-4 cells, induction of p21 and Mdm-2 was observed 1 day after infection, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effect of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 cells were most sensitive to killing by Ad-p53, with an IC50 of less than 2 multiplicity of infection; SW-1736 cells were intermediate in sensitivity; KAT-4 cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrease in IC50 values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating anaplastic thyroid cancer.
 ...
PMID:Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. 966 37

Anaplastic thyroid carcinoma is one of the most aggressive human malignancies. Outcomes of intensive multimodal therapy have been far from satisfactory. Furthermore, p53 gene dysfunction, often found in this type of cancer, is known to impair the efficacy of the therapeutic agents. Specific ligands for peroxisome proliferator activated receptor gamma (PPAR-gamma) induce growth suppression in some tumor cells. In this study, we investigated the role of PPAR-gamma in anaplastic thyroid cancer cell lines (OCUT-1, ACT-1). PPAR-gamma was expressed and functional in both cell lines. Activation of PPAR-gamma with its specific ligands, troglitazone and 15-deoxy-delta 12,14-prostaglandin J2, inhibited cell growth in a dose-dependent manner through inducing G1 cell cycle arrest. P53 protein expression differed in OCUT-1 and in ACT-1, though the levels stayed constant irrespective of ligand exposure in both cell lines. In contrast, p21 and p27 proteins were induced in a dose-dependent manner in both situations. This study showed that PPAR-gamma ligands were able to induce growth suppression in anaplastic thyroid cancer cells via a p53-independent, but p21- and p27-dependent cytostatic pathway. These tumor-suppressive effects of PPAR-gamma may provide a novel approach to the treatment of anaplastic thyroid cancer.
 ...
PMID:Peroxisome proliferator-activated receptor gamma activation induces cell cycle arrest via the p53-independent pathway in human anaplastic thyroid cancer cells. 1249 76

We have previously described a novel mechanism of p53 dysfunction, characterized by repression of mRNA and protein expression effectively leading to functional inactivation of wt p53 in SW-1736 human anaplastic thyroid cancer cells (pseudo-null p53). Here we demonstrated that treatment of SW-1736 cells with sub-cytotoxic concentrations of FR901228, a histone deacetylase (HDAC) inhibitor, results in marked induction of p53 mRNA and protein. The p53 induced by FR901228 was functional as evidenced by mdm-2 and p21 transactivation, and its further accumulation following DNA damage by doxorubicin. Furthermore, pretreatment with FR901228 sensitized SW-1736 cells to doxorubicin. This study validates the concept of pseudo-null p53, as a mechanism of p53 inactivation, and demonstrates that pseudo-null p53 can be rescued pharmacologically.
 ...
PMID:The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53. 1264 91

To establish a molecular targeting therapy for anaplastic thyroid carcinomas, we studied the effect of the specific tyrosine kinase inhibitor, STI571, on anaplastic thyroid cancer cell lines highly expressing c-ABL ARO (mutated p53) and FRO (undetectable p53). These lines showed marked inhibition of cell growth after treatment with STI571. In contrast, the growth of papillary thyroid cancer cell lines that harbor wild-type p53 and have low levels of c-ABL was not affected by STI571. Fluorescent-activated cell sorting analysis revealed that STI571 treatment increased the fraction of FRO and ARO cells in S and G(2)/M phases, respectively, indicating induction of S and G(2)/M transition arrest. These changes were accompanied by inhibition of c-ABL phosphorylation/activation and increased expression of p21(cip1) in FRO and p27(kip1) in both FRO and ARO cells. Treatment with STI571 also led to reduction of cyclin A, B1, and CDC2 levels. The growth of FRO cells implanted into immunocompromised mice was significantly inhibited by STI571. Taken together, these results suggest that selective suppression of c-ABL activity by STI571 may represent a potential anticancer strategy for p53-mutated undifferentiated thyroid carcinomas.
 ...
PMID:The selective tyrosine kinase inhibitor, STI571, inhibits growth of anaplastic thyroid cancer cells. 1455 95

The p73alpha protein is a functional homolog of the p53 tumor suppressor. Although the TP53 gene is frequently mutated in human cancers, the TP73 gene is rarely inactivated. We have found that p73alpha is highly expressed in a significant fraction of anaplastic thyroid cancer, whereas it is not detectable in normal thyroid epithelial cells or in papillary and follicular thyroid cancer cells. Interestingly, the tumor suppression function of p73alpha is actively restrained in anaplastic thyroid cancer cells. We have also found that c-Abl tyrosine kinase, an activator of p73, is excluded from the nucleus of p73alpha-positive thyroid cancer cells; whereas c-Abl undergoes nuclear-cytoplasmic shuttling in normal thyroid and p73-negative thyroid cancer cells. We constructed an AblNuk-FK506-binding protein (FKBP) fusion protein to enforce the nuclear accumulation of an inducible Abl kinase. Activation of this nuclear AblNuk-FKBP by dimerization with AP20187 in anaplastic thyroid cancer cells increased the levels of p73alpha and p21Cip1 and caused p73-dependent apoptosis. These results suggest subcellular segregation of c-Abl from p73 to be a strategy for disrupting the tumor suppression function of p73alpha.
 ...
PMID:Exclusion of c-Abl from the nucleus restrains the p73 tumor suppression function. 1271 88

Among the follicular neoplasms of the thyroid, the definition and nature of atypical adenoma have been confusing. Despite the original speculation about the biologic behavior of preinvasive malignancies, this term is currently used as an expression of uncertainty. To examine the molecular features of a typical adenoma, we analyzed the p53 genes in 2 atypical adenomas and 12 control lesions (6 typical follicular adenomas and 6 follicular carcinomas). Mutations of p53 were detected in the bizarre cells of the atypical adenomas, but not in the bland-looking follicular cells or in the control specimens. Both atypical adenomas showed an identical point mutation in codon 273 (CGT-->CAT), a common mutation in various human cancers, including anaplastic carcinoma of the thyroid. This finding supports the view that atypical follicular adenoma is a precursor of thyroid anaplastic carcinoma and suggests that "atypical adenoma" should not be used to express diagnostic uncertainty about the nature of a lesion.
 ...
PMID:Is atypical follicular adenoma of the thyroid a preinvasive malignancy? 1287 62

Anaplastic thyroid carcinomas are a highly aggressive and extremely lethal form of human cancer, but the biological characteristics related to their aggressive nature are not understood. Moreover, Gadd45 family proteins have been implicated in a variety of growth-regulatory mechanisms, including DNA replication and repair, G(2)/M checkpoint control, and apoptosis. In this study we found that Gadd45gamma RNA was present at significantly lower levels in anaplastic cancer cells, compared with normal primary cultured thyrocytes. In addition, the adenovirus-mediated reexpression of Gadd45gamma significantly inhibited the proliferation of anaplastic thyroid carcinoma cells, ARO, FRO, and NPA cells, which was attributed to apoptosis. Furthermore, the adenovirus-mediated delivery of Gadd45gamma gene in anaplastic thyroid cancer resulted in the inhibition of tumor growth in vivo. This in vitro and in vivo activity of the adenovirus-mediated transduction of CR6/Gadd45gamma, on anaplastic thyroid cancer cell growth suppression, was reminiscent of the effects of p53. This study demonstrates that the Gadd45gamma gene has potential use as a candidate gene for gene therapy in anaplastic thyroid cancer.
 ...
PMID:Gadd45gamma expression is reduced in anaplastic thyroid cancer and its reexpression results in apoptosis. 1291 87


1 2 3 4 5 6 Next >>