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)

In 54 lesions of gastric adenomas consisting of 31 low-grade adenomas (LGAs) and 23 high-grade adenomas (HGAs), 28 intramucosal carcinomas (IMCs), and 23 carcinomas invading the submucosa (SMCs), the expression of cell-cycle regulatory gene products (p53, p21/waf1, p27/kip1, and Ki-67) was studied using immunohistochemical techniques. Several lesions were also analyzed by the fluorescence in situ hybridization method. The overexpression of p53 was found in no LGAs and in 9% of HGAs, whereas a considerable number of cases showed an overexpression in IMCs (39%) and SMCs (43%). A reduced expression of p21/waf1 was present in only 4% of HGAs. Superficial eccentric positivity was present in all LGAs and 74% of HGAs, whereas it was present in 46% of IMCs and 4% of SMCs. P53-positive and p21/waf1-negative lesions, which were supposed to have a mutated p53 gene, were observed in no LGAs, in 4% of HGAs, in 11% of IMCs, and in 26% of SMCs. The expression of cyclin E was more frequently present in carcinomas than in adenomas. However, no high expression of cyclin E was observed among the adenomas. A reduced expression of p27/kip1 was encountered more frequently in carcinoma than adenoma. By a semiquantitative evaluation comparing adenoma and carcinoma in the same stomach, the increased degrees of both p21/waf1 and cyclin E were highlighted. A chromosome gain was detected among 7% of the adenomas and 85% of the carcinomas. In conclusion, the expressions of p53, p21/waf1, p27/kip1, and cyclin E were considered to be of great value for estimating the dysplastic progression of gastric adenomas. Especially, various aspects of protein expression, including its distribution and semiquantitative evaluation of positive cells, and a combined analysis with several proteins, may thus be useful as possible markers of dysplastic evolution in gastric adenomas.
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PMID:Expressions of cell-cycle regulatory gene products in conventional gastric adenomas: possible immunohistochemical markers of malignant transformation. 1074 68

Expression of cell cycle modulators at the G1-S boundary, the retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D1 as well as Ki-67 was investigated with 39 extrahepatic bile duct carcinomas (BDC). The Ki-67 labeling index (LI) was higher in cases with poor differentiation, lymph node metastasis and stage III or IV. Cyclin D1 overexpression was seen in 14 cases (35.8%). This phenomenon could be observed more frequently in cases of hilar carcinoma and with poor differentiation, perineural invasion, lymphatic invasion and lymph node metastasis. Furthermore, Ki-67 LI was higher in cyclin D1 overexpressing cases. p27 expression showed inverse relationships with Ki-67 LI, lymph node metastasis and aberrant p53 expression. Although p16 and p21 expression significantly correlated with lymph node metastasis and cyclin D1 overexpression, respectively, they were not related to Ki-67 LI. pRb expression was observed in all cases. Although the LI was lower in carcinoma of upper and middle bile ducts, no correlation was established between pRb expression and other clinicopathological parameters including Ki-67 LI. Aberrant p53 expression was observed in 13 cases (33.3%) and Ki-67 LI was significantly higher in these cases. These findings suggest that p27 and cyclin D1 strongly correlate with BDC proliferation and reflect the biological aggressiveness of this carcinoma.
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PMID:Expression and clinical significance of the G1-S modulators in carcinoma of the extrahepatic bile duct. 1076 77

Little is known about cell-cycle checkpoint activation by oxidative stress in mammalian cells. The effects of hyperoxia on cell-cycle progression were investigated in asynchronous human T47D-H3 cells, which contain mutated p53 and fail to arrest at G1/S in response to DNA damage. Hyperoxic exposure (95% O(2), 40-64 h) induced an S-phase arrest associated with acute inhibition of Cdk2 activity and DNA synthesis. In contrast, exit from G2/M was not inhibited in these cells. After 40 h of hyperoxia, these effects were partially reversible during recovery under normoxic conditions. The inhibition of Cdk2 activity was not due to degradation of Cdk2, cyclin E or A, nor impairment of Cdk2 complex formation with cyclin A or E and p21(Cip1). The loss of Cdk2 activity occurred in the absence of induction and recruitment of cdk inhibitor p21(Cip1) or p27(Kip1) in cyclin A/Cdk2 or cyclin E/Cdk2 complexes. In contrast, Cdk2 inhibition was associated with increased Cdk2-Tyr15 phosphorylation, increased E2F-1 recruitment, and decreased PCNA contents in Cdk2 complexes. The latter results indicate a p21(Cip1)/p27(Kip1)-independent mechanism of S-phase checkpoint activation in the hyperoxic T47D cell model investigated.
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PMID:Hyperoxia induces S-phase cell-cycle arrest and p21(Cip1/Waf1)-independent Cdk2 inhibition in human carcinoma T47D-H3 cells. 1077 7

Carcinogenesis is characterized by deregulation of the cell cycle. Although p53 is still the most important cell-cycle regulator in human malignancies, there is an increased body of evidence indicating that the aberrant expression of cyclins and cyclin-dependent kinase (CDK) inhibitors is considered as one of the most important events in malignant transformation of various human cancers. Among these cell-cycle regulators, the role of cyclin E and p27(KIP1) in the tumorigenesis of the uterine cervix has been poorly defined. Using formalin-fixed, paraffin-embedded cervical tissues, we investigated the expression of cyclin E and p27(KIP1) by immunohistochemistry, and human papillomavirus (HPV) types 16 and 18 by nested polymerase chain reaction (PCR) in 22 control cases, 23 cases with cervical intraepithelial neoplasia (CIN), and 45 patients with invasive cervical carcinoma (ICC). The p27 index (P27I) was significantly lower in patients with ICC and CIN compared to those with a normal cervix. Patients with either invasive cancer or CIN were found to have a significantly higher cyclin E index (CEI) than the controls (P<0.05). Our results were consistent with the concept that the deregulated expression of cyclin E and p27(KIP1) may play an important role in the neoplastic transformation of cervical carcinoma.
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PMID:Expression of cyclin E and p27(KIP1) in cervical carcinoma. 1077 28

Human papillomavirus (HPV) survives by reactivating DNA replication in post-mitotic cells. In the present study, we describe a mouse model of HPV-dependent disease. In these mice, DNA synthesis is activated in suprabasal keratinocytes, leading to acanthosis, parakeratosis and enhanced desquamation. The full-length E6/E7 transcript and two alternately spliced products are produced and in most lines the predominant product is E6*. In the present study, we examine the effects of E6/E7 on cell cycle regulatory protein expression. E6/E7 expression in mouse epidermis is correlated with increased levels of the p53, p21, p27, cdk2, cdk4, cdk6, cyclin D1 and cyclin E regulatory proteins. Hyperproliferation is also observed in the buccal mucosa and the tongue epithelia of E6/E7 mice, and p53 levels are markedly increased in these epithelia. These results suggest that the major changes in cell cycle regulatory protein expression are in response to the presence of E7 and that E6 has a lesser impact.
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PMID:Suprabasal expression of the human papillomavirus type 16 oncoproteins in mouse epidermis alters expression of cell cycle regulatory proteins. 1078 29

A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15(INK4b), p16(INK4a), p19( INK4d), and p21(Cip1) as well as other negative cell cycle regulators such as p53 and p19(ARF), implies that this senescence-related growth arrest is independent of the activity of p53, p19(ARF), p16(INK4a), and p21(Cip1), which are associated with replicative senescence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27(Kip1) can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27(Kip1)expression. In summary, these observations taken together suggest that p27(Kip1) is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.
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PMID:Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. 1079 51

Productive high-titer infection by human immunodeficiency virus type 1 (HIV-1) requires the activation of target cells. Infection of quiescent peripheral CD4 lymphocytes by HIV-1 results in incomplete, labile reverse transcripts and lack of viral progeny formation. An interplay between Tat and p53 has previously been reported, where Tat inhibited the transcription of the p53 gene, which may aid in the development of AIDS-related malignancies, and p53 expression inhibited HIV-1 long terminal repeat transcription. Here, by using a well-defined and -characterized stress signal, gamma irradiation, we find that upon gamma irradiation, HIV-1-infected cells lose their G(1)/S checkpoints, enter the S phase inappropriately, and eventually apoptose. The loss of the G(1)/S checkpoint is associated with a loss of p21/Waf1 protein and increased activity of a major G(1)/S kinase, namely, cyclin E/cdk2. The p21/Waf1 protein, a known cyclin-dependent kinase inhibitor, interacts with the cdk2/cyclin E complex and inhibits progression of cells into S phase. We find that loss of the G(1)/S checkpoint in HIV-1-infected cells may in part be due to Tat's ability to bind p53 (a known activator of the p21/Waf1 promoter) and sequester its transactivation activity, as seen in both in vivo and in vitro transcription assays. The loss of p21/Waf1 in HIV-1-infected cells was specific to p21/Waf1 and did not occur with other KIP family members, such as p27 (KIP1) and p57 (KIP2). Finally, the advantage of a loss of the G(1)/S checkpoint for HIV-1 per se may be that it pushes the host cell into the S phase, which may then allow subsequent virus-associated processes, such as RNA splicing, transport, translation, and packaging of virion-specific genes, to occur.
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PMID:Loss of G(1)/S checkpoint in human immunodeficiency virus type 1-infected cells is associated with a lack of cyclin-dependent kinase inhibitor p21/Waf1. 1079 78

Primitive, proliferating hematopoietic progenitors (defined as cytokine low-responding primitive progenitors; CLRPP), isolated from human CD34+ cells, expressed endoglin (CD105) and produced transforming growth factor-beta1 (TGF-beta1). Culture of CLRPP in serum-free conditions with anti-TGF-beta1 monoclonal antibody produced a substantial decrease in bcl-2 protein/RNA levels and a significant reduction of cloning and long-term culture-initiating cell (LTC-IC) activities. GATA-1 and PU.1 RNA levels were significantly up-regulated in anti-TGF-beta1-treated CLRPP, which generated an increased number of cells expressing CD15/CD11b/glycophorin-A. The described effects of TGF-beta1 neutralization were observed in the absence of any relevant effect on cell cycle; number of cell divisions; p53, c-myc, and p21 RNA levels; bcl-xL and bax protein levels; and c-myc/p16/p21/p107/Rb cell cycle-related protein levels. A relevant increase in p27 protein levels was observed in anti-TGF-beta1-treated CLRPP, suggesting a role for p27 in the regulation of the hematopoietic potential. The present study on human progenitors and previously reported data on TGF-beta1 knockout mice suggest that, at the autocrine level, the cell cycle inhibitor TGF-beta1 plays an important role in regulating the survival and differentiation of primitive proliferating hematopoietic progenitors by cell cycle-independent mechanisms.
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PMID:Modulation of bcl-2 and p27 in human primitive proliferating hematopoietic progenitors by autocrine TGF-beta1 is a cell cycle-independent effect and influences their hematopoietic potential. 1080 62

Non-squamous cell carcinoma is a rare but distinct neoplasm of the upper aerodigestive tract. Among these carcinomas, basaloid-squamous cell carcinoma (BSCC) has frequently been confused with adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma of the upper aerodigestive tract. In this study, we examined immunohistochemically the expression of differentiation-related substances, including cytokeratin (CK) subtypes, p53 and p27, and cell adhesion-related molecules E-cadherin and alpha-catenin to clarify the biological features of these neoplasms. We studied seven cases of BSCC of the oesophagus, five cases of ACC and seven cases of mucoepidermoid carcinoma. Squamous cell carcinoma and adenocarcinoma of the oesophagus and trachea were also studied for comparison. Among the cytokeratin subtypes examined, CK14, CK17 and CK19 immunoreactivity was detected in BSCC. ACC and mucoepidermoid carcinoma were immunopositive for CK8, CK14 and CK17 and for CK8, CK14, CK17 and CK19, respectively. These findings suggest that CK subtypes, especially CK8, CK14 and CK17, are useful in differentiating these malignancies. BSCC was more frequently associated with decreased E-cadherin and alpha-catenin immunoreactivity than ACC and mucoepidermoid carcinoma. Nuclear p53 immunoreactivity was detected more frequently in BSCC (5 out of 7) than in ACC (2 out of 5) and mucoepidermoid carcinoma (4 out of 7). There were no significant differences in p27 immunoreactivity among these carcinomas. Carcinoembryonic antigen (CEA) immunoreactivity was detected in mucoepidermoid carcinoma (2 out of 7), SCC (8 out of 11) and adenocarcinoma (9 out of 9), but it was not detected in BSCC (7) or ACC (5). Carbohydrate antigen 19-9 (CA19-9) immunoreactivity was detected only in mucoepidermoid carcinoma (4 out of 7) and adenocarcinoma, but not in BSCC, ACC, or SCC. These findings indicate that BSCC, ACC and mucoepidermoid carcinoma are distinct neoplasms arising in the upper aerodigestive tract. In addition, decreased expression of E-cadherin and alpha-catenin proteins and increased p53 expression in BSCC may be correlated with aggressive behaviour.
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PMID:Immunohistochemical study of basaloid squamous cell carcinoma, adenoid cystic and mucoepidermoid carcinoma in the upper aerodigestive tract. 1081 Apr 23

Studies on cell cycle regulation and cancer genetics have revealed that multiple cell cycle regulatory proteins play key roles in oncogenesis. These can be categorized in three sets. First; p16INK4-Cyclin D1-RB pathway, which controls G1 to S progression of the cell cycle, second; p53 pathway, which is involved in DNA damage repair, and third; p27KIP1 CDK inhibitor, a negative regulator of cell cycle, and decreased expression of which has been correlated to poor prognosis in cancer patients. Among these, p16INK4, RB and p53 are tumor suppressor genes, and p27 has been pointed out to be haplo-insufficient for tumor suppression. Involvement of these cell cycle regulatory proteins in lung cancer will be discussed.
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PMID:[Deregulation of cell cycle control in lung cancer]. 1082 44


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