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)

Cyclins are regulatory molecules that undergo periodic accumulation and destruction during each cell cycle. By activating p34cdc2 and related kinase subunits they control important events required for normal cell cycle progression. Cyclin A, for example, regulates at least two distinct kinase subunits, the mitotic kinase subunit p34cdc2 and related subunit p33cdk2, and is widely believed to be necessary for progression through S phase. However, cyclin A also forms a stable complex with the cellular transcription factor DRTF1 and thus may perform other functions during S phase. DRTF1, in addition, associates with the tumour suppressor retinoblastoma (Rb) gene product and the Rb-related protein p107. We now show, using biologically active fusion proteins, that cyclin A can direct the binding of the cdc2-like kinase subunit, p33cdk2, to complexed DRTF1, containing either Rb or p107, as well as activate its histone H1 kinase activity. Cyclin A cannot, however, direct p34cdc2 to the DRTF1 complex and we present evidence suggesting that the stability of the cyclin A-p33cdk2 complex is influenced by DRTF1 or an associated protein. Cyclin A, therefore, serves as an activating and targeting subunit of p33cdk2. The ability of cyclin A to activate and recruit p33cdk2 to DRTF1 may play an important role in regulating cell cycle progression and moreover defines a mechanism for coupling cell-cycle events to transcriptional initiation.
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PMID:Cyclin A recruits p33cdk2 to the cellular transcription factor DRTF1. 129 52

Wilms' tumour is a paediatric kidney cancer which, in a substantial number of cases, has been associated with a genetic predisposition. Susceptibility to Wilms' tumour can be manifested by the presence of bilateral tumours, and in rare cases by a family history of this tumour or by associated congenital malformations. Like retinoblastoma, Wilms' tumour has been postulated to result from the inactivation of a tumour suppressor gene, although genetic studies implicate more than a single genetic locus. The recent isolation of the WT1 gene, which maps to chromosome 11, band p13, has provided the first molecular clue to Wilms' tumorigenesis. WT1 is specifically inactivated in a number of Wilms' tumours, and mutations have been found in the germline of susceptible individuals. This gene appears to encode a transcription factor with complex alternative splices, whose expression is strictly regulated in the developing kidney. Functional studies will be required to elucidate the role of WT1 in normal kidney development and in tumorigenesis.
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PMID:Role of the WT1 gene in Wilms' tumour. 132 41

The HPVs associated with anogenital cancers encode two oncoproteins, E6 and E7. Both E6 and E7 can form specific complexes with tumour suppressor gene products. The E7 protein binds to the retinoblastoma tumour suppressor gene product pRB, with a preference for the underphosphorylated, "active" form of pRB. The E7 proteins derived from the "high risk" HPVs bind to pRB with a higher affinity than the E7 proteins from the "low risk" HPVs. The "high risk" HPV E6 proteins can associate with the p53 tumour suppressor protein. This interaction promotes the degradation of p53 in vitro, which presumably accounts for the very low levels of p53 in cervical carcinoma cell lines. The functional inactivation of pRB and p53 by the HPV oncoproteins E7 and E6, respectively, are likely to be important steps in cervical carcinogenesis, since mutations in the RB and p53 genes were detected in HPV negative but not HPV positive cervical carcinoma cell lines. Cytogenetic studies strongly suggest, however, that additional chromosomal changes may be necessary for carcinogenic progression of HPV induced anogenital lesions.
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PMID:Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. 132 42

The types of malignancy reported in carriers of constitutional ring chromosomes r(11), r(13), and r(22) are concordant with the chromosomal assignment of tumour suppressor loci associated with Wilms' tumour, retinoblastoma, and meningioma. It is suggested that the somatic instability of ring chromosomes may play a role in this association and that constitutional ring chromosomes may be a source for mapping of tumour suppressor loci with the potential for covering most or all of the human genome. The hypothesis predicts the presence of a locus on chromosome 10 associated with follicular carcinoma of the thyroid, in line with previous cytogenetic findings of rearrangements involving chromosome 10 in thyroid tumours, and a locus on chromosome 22 associated with testicular cancer. Development of neurofibromatoses (NF) that do not fulfil the clinical criteria of neurofibromatosis type 2 (NF2) in carriers with r(22) suggests either the presence of an additional NF locus on chromosome 22 or that ring chromosome mediated predisposition to somatic mutation of a specific tumour suppressor may be associated with atypical development of features usually associated with germline mutations.
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PMID:Constitutional ring chromosomes and tumour suppressor genes. 133 57

Typical carcinoid, atypical carcinoid, and small cell lung cancer (SCLC) fall within the spectrum of neuroendocrine lung neoplasms. This paper investigates the immunohistochemical expression of the products of tumour suppressor genes p53 and retinoblastoma (RB), together with proliferation (PCNA and Ki67) and neuroendocrine differentiation markers, in 14 typical carcinoids, ten atypical carcinoids, four borderline atypical carcinoid/SCLC, and 11 SCLC. We demonstrated that the phosphoprotein p53 and RB product can be immunolocalized on routine histological material. p53 protein was absent in all typical and atypical carcinoids, while it was abnormally expressed in eight SCLC and one borderline case. RB product was detected in all typical carcinoids and in two atypical carcinoids, while it was consistently absent in the other cases. PCNA-labelled cells were less than 4 per cent in typical carcinoids, about 40 per cent in atypical carcinoids, and over 70 per cent in SCLC. PCNA labelling index discriminates between typical and atypical carcinoids. Neuroendocrine differentiation was evaluated by a semi-quantitative method: a mean score value was obtained, which was high in typical carcinoids, intermediate in atypical carcinoids, and low in SCLC. Our data was obtained, which was high in typical carcinoids, intermediate in atypical carcinoids, and low in SCLC. Our data show that the decrease in neuroendocrine features from typical carcinoid to SCLC is paralleled by an increase in proliferative activity and by an altered expression of tumour suppressor gene products. The above findings have diagnostic relevance.
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PMID:Tumour suppressor gene products, proliferation, and differentiation markers in lung neuroendocrine neoplasms. 135 31

Inactivation of tumour suppressor genes may be an important aetiological factor in many human cancers including breast. In a study of 197 breast cancer patients, tumour tissue was snap-frozen at the time of surgery and immunohistochemical labelling for p53 protein and retinoblastoma (Rb) gene product carried out using an indirect immunohistochemical technique. Tumours were scored by two independent observers for the intensity of nuclear staining for each antibody. Expression of p53 protein showed a significant association with a shorter time to relapse (P = 0.03) and death (P = 0.02) (log rank test). p53 expression did not correlate with nodal status but showed a significant association with high tumour grade (P = 0.001). Rb gene expression showed no relationship to relapse or survival but loss of expression showed a significant correlation with positive lymph node status. The manner by which these proteins might act to determine tumour behaviour remains to be established.
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PMID:Retinoblastoma and p53 gene expression related to relapse and survival in human breast cancer: an immunohistochemical study. 145 67

The retinoblastoma protein (pRB) is thought to act as a tumour suppressor which is inactivated by phosphorylation. In quiescent (G0) cells pRB exists in a hypophosphorylated form (pRB110), but proliferating cells in G1 contain a significant proportion of phosphorylated pRB (pRB112-114). Studies of synchronized or elutriated cells have suggested that the phosphorylated forms of pRB disappear as cells pass from G2/M to G0/G1 and that pRB is phosphorylated again to pRB114 at the G1/S border. In this study we used two-parameter flow cytometry and cell sorting to isolate cycling cells in early and late G1 (G1A and G1B), and we show that partially phosphorylated pRB is present in cycling human lymphoid cells even in G1A. These G1A cells contain intermediate forms of pRB which become further phosphorylated to pRB112-114 as cells pass into G1B. Therefore pRB is at least partially phosphorylated from early G1 onwards. Cell cycle arrest by alpha-interferon (alpha-IFN) results in an accumulation of cells in both G1A and G1B, and these cells contain mainly pRB110. Since pRB110 is thought to prevent cell proliferation, the cytostatic effect of alpha-IFN may therefore occur by preventing the initial phosphorylation of pRB during or prior to G1A.
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PMID:The retinoblastoma protein is partially phosphorylated during early G1 in cycling cells but not in G1 cells arrested with alpha-interferon. 156 75

Some of the cellular changes underlying the presentation of cancer in a patient can already be understood in terms of mutations affecting specific gene functions. So far, only a few of the mutated genes responsible for carcinogenesis have been identified and these are chiefly involved in deregulation of cell growth rather than with the processes of invasion and metastasis. Proto-oncogenes are important cellular genes which can acquire gain in function mutations as random events in somatic cells. In their mutated, activated forms they are called cellular oncogenes or c-oncs. This distinguishes them from homologous DNA sequences captured by viruses from host cells in the course of retroviral evolution that cause cancers in animal hosts (viral oncogenes or v-oncs). In recent years, loss of function mutations have been identified in regulatory genes that normally serve to constrain cell growth. These are called tumour suppressor genes. Loss of function mutations may be transmitted in the germline, as in hereditary retinoblastoma, or arise de novo in somatic cells. The normal molecular mechanisms disrupted by mutations in tumour suppressor genes include processes regulating progression through the cell cycle.
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PMID:What are cancer genes, and how do they upset cell behaviour? 156 75

Retinoblastoma, the most common intraocular malignancy of children, has served as an important paradigm for understanding the events involved in neoplastic transformation. Much of the contemporary molecular description of human cancers stems directly from experimental approaches first developed to study this childhood tumour. This analytical methodology has demonstrated a major role for heritable predisposition in tumourigenesis, provided evidence for tissue pleiotropy of cancer genes, and revealed a more precise estimation of the number, activity, and location of other tumour suppressor loci.
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PMID:Molecular genetics in the pathology and diagnosis of retinoblastoma. 166 90

Four chromosomal regions were tested for loss of constitutional heterozygosity in primary tumours from 85 Icelandic breast cancer patients. Loss of heterozygosity and other types of gene rearrangements were observed in 37% of informative cases at the retinoblastoma locus, RB1, on chromosome 13q. Allele losses on chromosome 17 were tested with two polymorphic probes on 17p and two on 17q. Loss of heterozygosity or other types of genetic rearrangement were detected in 43.5% of cases on 17p near the p53 gene and 40.5% on 17q. In our study abnormalities at the RB1 locus and on chromosome 17 frequently occurred together, indicating that the coincident inactivation of more than one tumour suppressor gene may, in some cases, play a part in tumour formation. No significant correlation was found between these losses and clinico-histological parameters. Family history of breast cancer was found to be more common among patients with RB1 deletions and this trend was strengthened in cases where there were deletions at both the RB1 locus and on chromosome 17.
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PMID:Loss of heterozygosity at selective sites on chromosomes 13 and 17 in human breast carcinoma. 174 6


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