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 molecular basis for the transition of carcinoma of the prostate from androgen-dependent to androgen-independent growth is largely unknown. Currently for example, it is not clear whether the androgen-independent phenotype is a result of selection of a subgroup of genetically distinct prostate tumour cells which are already hormone-resistant or a genetic adaptation of prostate tumour cells to the hormone therapy itself. It has also been established that prostate tumour transformation is a result of homeostatic control defects, a line of thinking directed toward elucidating the apoptotic profile of prostate tumour cells that may be important in determining prognosis, response to therapy and illness progression. Main consideration in this part of rewiev is given to the role of tumour suppressor genes pRb and PTEN and also the natural inhibitors of cyclin dependent kinases - proteins p21(Waf1/Cip1) and p27(Kip1). Attention is also given to the role of FAS-mediated pathways in apoptosis induction.
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PMID:The significance of key regulators of apoptosis in the development and prognosis of prostate carcinoma. II. Products of suppressor genes Rb and PTEN, CDKI, Fas. 1503

Inhibition of cyclin A- and cyclin E-associated cyclin-dependent kinase-2 (CDK2) activities is an effective way of selective induction of apoptotic cell death via the E2F pathway in tumour cells. The cyclin groove recognition motif (CRM) in the natural CDK-inhibitory (CDKI) tumour suppressor protein p27KIP1 was used as the basis for the design and synthesis of a series of cyclic peptides whose biological activity and structural characterisation by NMR and X-ray crystallography is reported. Whereas linear p27KIP1 sequence peptides were comparatively ineffective, introduction of side chain-to-tail constraints was found to be productive. An optimal macrocyclic ring size for the conformational constraint was determined, mimicking the intramolecular H-bonding system of p27. Molecular dynamics calculations of various macrocycles suggested a close correlation between ring flexibility and biological activity. Truncated inhibitor peptide analogues also confirmed the hypothesis that introduction of a cyclic conformational constraint is favourable in terms of affinity and potency. The structural basis for the potency increase in cyclic versus linear peptides was demonstrated through the determination and interpretation of X-ray crystal structures of complexes between CDK2/cylin A (CDK2A) and a constrained pentapeptide.
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PMID:Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes. 1545 44

Tumour cells are characterised by uncontrolled growth due to alterations in the genes that play a key role in cell repair systems and apoptosis: pro-mitotic oncogenes such as cyclin D1, and tumour suppressor genes such as p27. Recent studies have demonstrated that these genes are involved in different epithelial neoplasms and that their expression is generally associated with prognosis. The aim of this immunohistochemical study was to analyse the clinical relevance of cyclin D1/p27 co-expression in a homogeneous series of 132 laryngeal squamous cell carcinomas. Multivariate analysis showed that cyclin D1 and p27 were the only statistically significant predictors of disease-free and overall survival. In relation to the simultaneous expression of p27 protein and cyclin D1, the patients with a cyclin D1+/p27-phenotype had the poorest disease-free and overall survival rates. On the basis of these immunohistochemical results, it was possible to select a subgroup of patients with a high risk of recurrence and poor prognosis to undergo more extended surgical treatment and/or combination antitumoral therapeutic procedures.
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PMID:Prognostic significance of P27 and cyclin D1 co-expression in laryngeal squamous cell carcinoma: possible target for novel therapeutic strategies. 1567 66

Oral squamous cell carcinoma (OSCC) is the most frequent malignant neoplasm of the head and neck region. Conversion of normal cells to cancer cells is achieved through a multi-step process that is closely associated with the accumulation of multiple gene changes including both oncogenes and tumour suppressor genes. The proliferation and progression of cancer may be caused by abnormalities of various positive and negative cell cycle regulators. Cell cycle progression is positively regulated by multiple cyclins and cyclin-dependent kinases (Cdks) and cyclin/Cdk complexes are negatively regulated by a number of Cdk inhibitors including p27. p27 is a Cdk inhibitor and plays an important role in negative regulation of the cell cycle during G0 and G1 phases. Degradation of p27 is a critical event for the G1/S transition and occurs through ubiquitination by SCF(Skp2) and subsequent degradation by the 26S proteasome. It has been revealed that down-regulation of p27 is frequently found in various cancers, including OSCC, and is due to an enhancement of its degradation. Importantly, down-regulation of p27 is well associated with its malignancy including poor prognosis in various cancers. Moreover, aggressive human cancers express low levels of p27 because of its decreased stability. More recent evidence suggests that Skp2 and Cks1, the specific recognition factors for p27 ubiquitination, have oncogenic properties. This review will focus on down-regulation of p27 and mechanism of its down-regulation in OSCC.
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PMID:Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinoma. 1569 11

The development of endometrial carcinoma (EC) is a multiple-step process, which includes inactivation of tumour suppressor genes, activation of oncogenes, and disturbance of cancer-related genes. Recent studies have shown that the circadian cycle may influence cancer development and prognosis. In this study, the expression of a circadian gene, PER1, was examined in 35 ECs and paired non-tumour tissues by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Expression levels of PER1 were significantly decreased in EC, and mutational analysis of the coding regions, together with methylation analysis of cytosine-phosphate guanosine (CpG) sites in the promoter area, was performed to investigate the possible mechanisms. The analyses detected four single nucleotide polymorphisms in both tumour and non-tumour tissues, which had no relationship with the expression of PER1. In the promoter area of the PER1 gene, the CpG sites were methylated in 31.4% of ECs, but in 11.4% of paired non-tumour tissues (p < 0.05). These results suggest that the down-regulation of PER1 expression in EC was partly due to inactivation of the PER1 gene by DNA methylation of the promoter and partly due to other factors. Analysis of the relationships between the expression of PER1, P53, c-MYC, cyclin A, cyclin B, and cyclin D1 showed no definite relationship. These results suggest that down-regulation of the PER1 gene disrupts the circadian rhythm, which may favour the survival of endometrial cancer cells.
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PMID:Abnormal expression of period 1 (PER1) in endometrial carcinoma. 1580 76

Deletions of the short arm of chromosome 9 have been observed in many tumours and cell lines. This chromosomal region is frequently targeted during malignant transformation because it contains at least two known tumour suppressor genes: p16(INK4) and p15(INK4B). p16(INK4A) acts as a negative cell cycle regulator by inhibiting G1 cyclin-dependent kinases that phosphorylate the retinoblastoma protein and therefore block the progression of the cell cycle from G1 to S phase. The role of p16(INK4A) in the development of synovial sarcoma has not been comprehensively investigated. Ten samples of synovial sarcomas were examined for allelic imbalance/loss of heterozygosity (AI/LOH) of the 9p region and p16 protein expression. DNA was isolated from microdissected sections of normal and tumour cells, amplified by polymerase chain reaction and analysed for AI/LOH by using six microsatellite markers that map to the 9p region. Immunohistochemistry for p16 expression was done. AI/LOH with at least one microsatellite marker on 9p21 was detected in six of ten samples. The most frequent allelic deletions were observed within the coding sequence of p16(INK4A). Loss of p16 immunoreactivity was detected in eight samples, six of which showed evidence of alterations at 9p21 region. These findings suggest a possible role of loss of p16(INK4A) in the development of synovial sarcoma.
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PMID:Loss of p16INK4A expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected synovial sarcomas. 1608 60

The pRb (retinoblastoma protein) tumour suppressor protein has a crucial role in regulating the G1- to S-phase transition, and its phosphorylation by cyclin-dependent kinases is an established and important mechanism in controlling pRb activity. In addition, the targeted acetylation of lysine (K) residues 873/874 in the carboxy-terminal region of pRb located within a cyclin-dependent kinase-docking site hinders pRb phosphorylation and thereby retains pRb in an active state of growth suppression. Here, we report that the acetylation of pRb K873/874 occurs in response to DNA damage and that acetylation regulates the interaction between the C-terminal E2F-1-specific domain of pRb and E2F-1. These results define a new role for pRb acetylation in the DNA damage signalling pathway, and suggest that the interaction between pRb and E2F-1 is controlled by DNA-damage-dependent acetylation of pRb.
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PMID:DNA-damage-responsive acetylation of pRb regulates binding to E2F-1. 1637 12

The tumour suppressor gene, TP 53 (commonly also called p53) has multiple, important cellular functions involving control of apoptosis, downstream cell cycle regulation via p21 and cyclin dependent kinases, and control of tumour angiogenesis. Somatic mutation of TP 53 is considered to be the most common genetic mutation in human cancer. Mutations of the gene are associated with drug resistance and poor patient prognosis in human cancers. Immunohistochemistry to detect mutated TP 53 is unreliable and molecular biology approaches are therefore preferable for its assessment. This chapter describes protocols for the 'gold standard', but perhaps complex and time consuming, methods for sequencing TP 53, by cDNA and genomic based sequencing techniques.
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PMID:Sequencing of the tumor suppressor gene TP 53. 1649 13

The transformation of melanocytes to melanoma cells is characterised by abnormal proliferation resulting from alterations in cell cycle regulatory mechanisms. This occurs through alterations in the two major cell cycle regulatory pathways, the retinoblastoma (Rb) and p53 tumour suppressor pathways. This review summarises the current knowledge of alterations in these two pathways at G1/S transition and specifically the role of the key cell cycle regulatory proteins pRb, p16INK4a (p16), cyclin D1, p27Kip1 (p27), p53 and p21Waf1/Cip1 (p21) in the pathogenesis of melanoma. It also considers their prognostic significance. Current data indicate that alterations of cyclin kinase inhibitor (cdki) levels are implicated in the pathogenesis of melanoma and may be useful prognostic markers. However, large validation studies linked to comprehensive clinical follow up data are necessary to clarify the prognostic significance of cell cycle regulatory proteins in individual patients.
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PMID:The role of cell cycle regulatory proteins in the pathogenesis of melanoma. 1691 16

Parathyroid carcinoma (PC) is an uncommon finding, accounting for only 1-2% of patients with primary hyperparathyroidism (HPT), but a relatively higher incidence has been reported in Italy and Japan. The etiology of the tumour remains unclear, but molecular analysis studies have hypothesised the involvement of mutations of several genes in the pathogenesis of PC, including the oncogene cyclin Dl or PRADI located at the chromosome 13, the retinoblastoma and the p53 tumour suppressor gene. The clinical presentation of patients with PC is mainly related to the increased secretion of PTH rather than to the tumour burden. The pre-operative diagnosis of malignancy is very difficult to obtain, and, thus, intra-operative recognition of PC is mandatory. However, reliable signs of malignancy are rarely detectable. Probably, only vascular invasion, that correlates with tumour recurrence and metastases, should be considered useful in confirming malignancy, although both Ki-67 and Cyclin D1 have been recently used to aid in the definitive diagnosis. The en bloc resection of the tumour, together with ipsilateral thyroid lobe and adjacent structures, only if involved, avoiding any capsular rupture of the mass, represents the gold standard of surgical treatment of patients. Although the PC has traditionally been considered as a radioresistant tumour, there are some retrospective data holding a possible benefit from post-operative irradiation. No cytotoxic regimen with proven efficacy is currently available for patients with PC, but since hypercalcemia is ultimately the most frequent cause of death, several studies have suggested the usefulness of bisphosphonates (i.e., clodronate, pamidronate and zoledronate), calcitonin, and calcimimetic agents (i.e., cinacalcet) in patients with PC and severe hypercalcemia. In conclusion, PC is a rare malignancy and the NCDB survey reports an overall five- and ten-year survival rate of 85% and 49%, respectively. However, it is very difficult to predict the clinical behaviour of patients with PC and probably the ultimate prognosis depends on successful resection of the tumour at the initial surgery.
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PMID:Parathyroid cancer: etiology, clinical presentation and treatment. 1721 44


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