Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical management of pancreatic disease is often hampered by a lack of tissue diagnosis. Endoscopic pancreatography offers the opportunity to investigate exfoliated cells. However, the significance of mere cytological investigation is compromised by an insufficient sensitivity. The evaluation of the molecular background of carcinogenesis hopefully is capable of providing more sensitive diagnostic markers. The p16INK4a-/retinoblastoma tumour-suppressive pathway has been shown to be involved in the development of near to all pancreatic neoplasms. p14ARF is another tumour suppressor located in the immediate neighbourhood of p16INK4a. Promoter methylation has been demonstrated to be a major inactivating mechanism of both genes. We sought to further evaluate the role of the gene locus INK4a methylation status in the endoscopic differentiation of chronic inflammatory and neoplastic pancreatic disease. Pancreatic fluid specimens of 61 patients with either pancreatic carcinoma (PCA: 39), chronic pancreatitis (CP: 16) or a normal pancreatogram (NAD: 6) were retrieved. In order to detect methylation of either the p14ARF or the p16INK4a promoter a methylation-specific PCR protocol was applied. While 19 out of 39 patients with PCA showed p16 promoter methylation (49%), none of the 16 patients with CP revealed p16 promoter methylation. p14ARF methylation was found in a lower percentage of PCA specimens and in none of the samples of patients with CP. These results suggest a specific significance of INK4a for the development of malignant pancreatic disease. Our data further indicate a potential role for INK4a methylation as a diagnostic marker in the endoscopic differentiation of benign and malignant pancreatic disease.
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PMID:Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions. 1261 May 6

Inactivation of the p53 function is a common event in cancer. Approx. 50% of human tumours express mutant p53 and there is evidence that in others, including many childhood tumours, p53 function is impaired in other ways. These defects on p53 function may be due to the alteration of cellular factors that modulate p53 or to the expression of viral oncoproteins. Radiotherapy and many of the chemotherapeutic drugs currently used in cancer treatment are potent activators of p53. However, most of these therapies have a serious drawback; that is, the long-term consequences of their DNA-damaging effects. Understanding the mechanisms regulating p53 stability is crucial for the development of new strategies to activate p53 non-genotoxically. Here we describe the effect of a potent activator of the p53 response, the nuclear export inhibitor leptomycin B, on Mdm2 degradation and we provide evidence for the oligomerization of the p14ARF tumour suppressor and Mdm2 inhibitor in response to oxidative stress.
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PMID:Protecting p53 from degradation. 1265 67

Deregulation of the RB pathway is shared by most human malignancies. Components upstream of the retinoblastoma tumour suppressor (pRB), namely the INK4 family of cyclin-dependent kinase (CDK) inhibitors, the D-type cyclins, their partner kinases CDK4/CDK6, and pRB as their critical substrate, are differentially targeted in diverse types of cancer. An 'unorthodox' spectrum of defects within this cascade occurs in testicular germ cell tumours (TGCTs), including silencing of pRB transcription, overexpression of cyclin D2, and loss of p18INK4c. To improve understanding of the role of this pathway in spermatogenesis, and its subversion in TGCTs, we examined immunohistochemical expression patterns of CDK4, p16INK4a, p15INK4b, and pRB, and established an in situ assay for cyclin D-mediated phosphorylation of serine795, a phosphorylation event critical for neutralization of pRB's growth-restraining ability. pRB was expressed throughout adult spermatogenesis and was detectable in teratomas, but was absent or grossly reduced in carcinoma in situ (CIS) and most seminomas and embryonal carcinomas. Unexpectedly, we also found that pRB was absent from fetal human gonocytes, the candidate target cell for all types of TGCTs. Thus, rather than a tumorigenesis-promoting loss of pRB, the lack of pRB in TGCTs likely reflects its developmental control. Widespread expression of p15INK4b, found in normal testes, was preserved in TGCTs. In contrast, p16INK4a was lost or reduced in large subsets of TGCTs. CDK4 was expressed in normal spermatogonia, CIS, and invasive TGCTs, as was serine795-phosphorylated pRB. Our data on expression of pRB support the plausible origin of TGCTs from fetal gonocytes, and the serine795 phosphorylation demonstrates that the cyclin D-dependent kinases are active, and neutralize pRB in spermatogonia and in those TGCTs that express pRB. We hope that this study will inspire further immunohistochemical applications of phosphospecific antibodies in pathology, and examination of the RB pathway defects in relation to curability of TGCTs.
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PMID:Deregulation of the RB pathway in human testicular germ cell tumours. 1275 35

Nasopharyngeal carcinoma (NPC) is the most tightly Epstein-Barr virus (EBV)-associated tumour. The EBV oncoprotein latent membrane protein 1 (LMP1) is frequently expressed in NPC tumours and may play a role in the genesis of the disease. NPC tumours often exhibit loss of expression (by deletion or methylation) of the INK4a locus, which encodes the tumour suppressor genes p16INK4a and p14ARF. To investigate the contribution of LMP1 and INK4a loss to tumourigenesis, skin chemical carcinogenesis was conducted using PyLMP1 and INK4a null mice. Surprisingly, INK4a null mice developed significantly fewer papillomas than wild-type mice, nevertheless, the papillomas that did develop grew faster and converted more rapidly to carcinoma than controls. This indicates that while loss of the INK4a locus plays an important role in the later stages of tumourigenesis, initially its loss inhibits papilloma formation. Conversely, LMP1 promoted papilloma formation but paradoxically inhibited papilloma growth. Using cross-breeds, it was found that LMP1 cooperates with loss of the INK4a locus during epithelial tumourigenesis. The expression of LMP1 overcame the inhibition of papilloma formation observed in INK4a null mice, whilst the loss of the INK4a locus counteracted the inhibition of papilloma growth rate found in PyLMP1 mice. This suggests that LMP1 mediates the inhibition of papilloma growth via one or both of the INK4a locus products. Intriguingly, mice heterozygous for INK4a loss showed lesion growth rates intermediate between wild-type and null, demonstrative of haploinsufficiency. We propose that LMP1 acts at the early stages in carcinogenesis to promote the development of benign tumours and that early reduction of INK4a locus expression allows these lesions to expand in size. In addition, loss of the INK4a locus accelerates the development of a more aggressive lesion. Conversely, complete loss of the INK4a locus in an otherwise normal cell might inhibit lesion formation.
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PMID:The latent membrane protein 1 of Epstein-Barr virus and loss of the INK4a locus: paradoxes resolve to cooperation in carcinogenesis in vivo. 1280 17

The INK4a/ARF locus encodes two proteins whose expression limits cellular proliferation. Whilst the biochemical activities of the two proteins appear very different, they both converge on regulating the retinoblastoma and p53 tumour suppressor pathways. Neither protein is required for normal development, but lack of either predisposes to the development of malignancy. Both proteins have also been implicated in the establishment of senescence states in response to a variety of stresses, signalling imbalances and telomere shortening. The INK4a/Arf regulatory circuits appear to be partially redundant and show evidence of rapid evolution. Especially intriguing are the large number of biological differences documented between mice and man. We review here the brief history of INK4a/Arf and explore possible links with organismal aging and the evolution of longevity.
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PMID:Involvement of the INK4a/Arf gene locus in senescence. 1288 6

Two proteins, p16INK4A and p14ARF, originating from the same gene locus CDKN2A, use different promoters and alternative reading frames. p16INK4A is translated from alpha transcript and p14ARF is from beta transcript. These two proteins, which are inactivated in some human malignancies, are possible tumour suppressor candidates. In this study, we investigated the expression of p16INK4A and p14ARF mRNAs in haematological malignancies. We studied eight normal bone marrow samples, three reactive granulocytic hyperplasia patients, and 21 haematological malignancy patients, including seven acute myelogenous leukaemia, four acute lymphoblastic leukaemia, five myelodysplastic syndrome, five chronic myelogenous leukaemia (CML). p16INK4A and p14ARF mRNA expression was assayed by reverse transcriptase polymerase chain reaction. Normal bone marrows and reactive granulocytic hyperplasia showed barely detectable expression of either mRNA. In contrast, p16INK4A and p14ARF mRNA expression was abnormally increased in patients with haematological malignancies. Especially in CML, overexpression of p16INK4A and p14ARF mRNAs was more frequent than in controls (80 and 60%, respectively, P < 0.05). In conclusion, p16INK4A and p14ARF mRNA expression was frequently increased in haematological malignancies, especially in CML. We suggest that overexpression of these mRNAs may be related to the pathogenesis of haematological malignancies.
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PMID:Overexpression of p16INK4A and p14ARF in haematological malignancies. 1527 71

Hypermethylation of cytosines in CpG-rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 (p16(INK4a)/CDKN2A) and p14 (p14(ARF)) by methylation-specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco-related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3-22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9-17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex-smokers.
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PMID:Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. 1291 69

Enteropathy-type T-cell lymphoma (ETL) and ulcerative jejunitis (UJ) are rare disorders often occurring in patients with coeliac disease. The genetic events associated with the accumulation of intraepithelial lymphocytes in coeliac disease and tumour development are largely unknown. Deletions at chromosome 9p21, which harbours the tumour suppressor genes p14/ARF, p15/INK4b, and p16/INK4a, and 17p13, where p53 is located, are associated with the development and progression of lymphomas. To examine whether deletions at 9p21 and 17p13 play a role in ETL, 22 cases of ETL and seven cases of UJ were screened for loss of heterozygosity (LOH) by tissue microdissection and polymerase chain reaction (PCR) analysis for microsatellite markers. Furthermore, p53 and p16 protein expression was examined by immunohistochemistry. In addition, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis for detection of mutations in exons 5-8 of the p53 gene was performed in five cases of ETL and three cases of UJ. LOH was found in at least one microsatellite marker at the 9p21 locus in 8 of 22 (36%) ETLs, but not in UJ. Five of nine (56%) tumours composed of large cells showed LOH at 9p21, as opposed to two of eight (25%) tumours with small- or medium-sized cell morphology. The region spanning the p14/p15/p16 gene locus was most frequently affected (five cases); LOH at these markers coincided with loss of p16 protein expression in all of these cases. p53 overexpression was demonstrated in all ETLs examined and in four of seven cases of UJ. However, no alterations of the p53 gene were detected by LOH or PCR-SSCP analysis. The results of this study show that LOH at chromosome 9p21 is frequent in ETL, especially in tumours with large cell morphology; this finding suggests that gene loss at this locus may play a role in the development of ETL.
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PMID:Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma. 1474 9

Although much less prevalent than its nonmelanoma skin cancer counterparts, cutaneous malignant melanoma (CMM) is the most lethal human skin cancer. Epidemiological and biological studies have established a strong link between lifetime exposure to ultraviolet (UV) light, particularly sunburn in childhood, and the development of melanoma. However, the specific molecular targets of this environmental carcinogen are not known. Data obtained from genetic and molecular studies over the last few years have identified the INK4a/ARF locus as the "gatekeeper" melanoma suppressor, encoding two tumour suppressor proteins in human, p16 $^{\text{INK4a}}$ and p $14^{\text{ARF}}$ . Recent developments in molecular biotechnology and research using laboratory animals have made a significant gene breakthrough identifying the components of the p16 $^{\text{INK4a}}$ /Rb pathway as the principal and rate-limiting targets of UV radiation actions in melanoma formation. This review summarizes the current knowledge of the molecular mechanisms involved in melanoma development and its relationship to sunlight UV radiation.
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PMID:Towards a Better Understanding of the Molecular Mechanisms Involved in Sunlight-Induced Melanoma. 1568 39

As combinations of genetic and/or epigenetic alterations occurring during salivary gland carcinogenesis are largely unknown, we here analyzed 36 salivary gland carcinomas (SGCs) for changes in INK4a/ARF, RB1, p21, p27, PTEN, p53, MDM2 and O6-MGMT genes using methylation specific PCR (MSP), loss of heterozygosity (LOH) assays and mutational analysis with immunohistochemistry (IHC), as well as histone H3 and H4 acetylation status. The RB1 gene was found to be the most frequently methylated (41.7% of cases), while methylation of p27(Kip1) and O6-MGMT were less frequent 8.3% and 5.6%, respectively). Two other genes, p21(Waf1) and PTEN, were unmethylated in the SGCs examined. RB1 methylation significantly correlated with loss of expression as determined by IHC (P=0.03), and also a poor prognosis (P=0.02). p53 mutations were found in 8 cases (22.2%), coupled with p14ARF hypermethylation in two cases. LOH in INK4a/ARF and the RB1 locus was observed in 33.3% and 28.6% of the lesions, respectively. There was no correlation between 9p21 LOH and methylation of the INK4a/ARF gene. Promoter hypermethylation of RB1 coupled with LOH was evident in three samples immuno-negative for RB1. Acetylation of histone H3 and H4 was detected in 6 and 5 cases, respectively. These findings indicate that epigenetic silencing of tumour suppressor genes via promoter hypermethylation might be crucial for salivary gland carcinogenesis, particularly in the RB1 gene. Thus epigenetic events including methylation and acetylation as well as genetic alterations may have important contributions.
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PMID:Genetic and epigenetic alteration profiles for multiple genes in salivary gland carcinomas. 1569 18


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