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)

Loss of a whole chromosome 5 or deletion of 5q are recurring abnormalities in malignant myeloid neoplasms. Chromosomal loss or deletion are the hallmarks of tumour suppressor genes, suggesting that a gene(s) located on 5q may function as a leukaemia suppressor gene. To determine the location of genes on 5q that may be involved in myeloid leukaemogenesis, we examined the breakpoints of the del(5q) in a series of 117 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. A striking number of genes encoding haematopoietic growth factors have been mapped within or adjacent to the critical region. These include the genes encoding CSF-2, IL-3, IL-4, IL-5 and IL-9. By using fluorescence in situ hybridization, we have refined the localization of these genes to 5q31.1. To facilitate the identification of a tumour suppressor gene on 5q, we are currently preparing a physical map of 5q31. With FISH analysis of a series of cosmid and phage clones, we identified a number of clones within 5q31. By hybridizing these probes to metaphase cells with a del(5q) involving proximal or distal breakpoints within 5q31, we have narrowed the critical region to a small segment of 5q31 containing eight of the cosmids. In addition, we found that the five growth factor genes are excluded from this region. We have used dual colour FISH to determine the order of these cosmids, the order of the known genes mapped to 5q23-33 and the relationship of these genes to the critical region. To date, mutations of these genes in leukaemia cells have not been identified. The clinical features of myeloid diseases associated with a del(5q) are variable (RA 5q- syndrome v. AML); thus, once the involved gene is identified, it will be important to determine whether the same gene is involved in both types of myeloid disorders.
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PMID:Deletions of chromosome 5 in malignant myeloid disorders. 145 Nov 9

At the present time, two general mechanisms account for deregulation and subsequent oncogenic conversion of transcriptional proteins in human leukaemias. One involves quantitative alterations in expression, suggesting that activity of the involved factors is primarily controlled by their accessibility within the cell. Neoplastic transformation may result from excessive expression or, conversely, complete loss of functional products (eg tumour suppressor proteins not described here). The second mechanism involves mutation by protein fusion (or truncation) and illustrates the modular composition of transcriptional proteins. The loss or inappropriate combination of specific modules creates chimaeric proteins with presumably altered transcriptional properties that may contribute to the neoplastic phenotype. Both mechanisms underscore the importance of cognate interactions, particularly heterodimerization between various transcriptional proteins with other members of the transcription complex. Future efforts will continue to focus on the interactions of oncogenic transcription factors with other cellular proteins and their biologically relevant target genes.
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PMID:Transcription factors in human leukaemias. 145 Nov 16

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 p53 tumour suppressor protein is phosphorylated by several protein kinases, including casein kinase II. In order to understand the functional significance of phosphorylation by casein kinase II, we have introduced mutations at serine 386 in mouse p53, the residue phosphorylated by this kinase, and investigated their effects on the ability of p53 to arrest cell growth. Replacement of serine 386 by alanine led to loss of growth suppressor activity, while aspartic acid at this position partially retained suppressor function. These data suggest that the anti-proliferative activity of p53 is activated by phosphorylation at serine 386, and establish a direct link between the covalent modification of a growth suppressor protein and regulation of its activity in mammalian cells.
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PMID:Mutation of the casein kinase II phosphorylation site abolishes the anti-proliferative activity of p53. 145 21

The tumour suppressor gene p53, located on the short arm of chromosome 17, encodes for a nuclear protein which regulates cell proliferation by inhibiting cells entering S-phase. p53 mutations are alleged to be the commonest genetic abnormality in human cancer. We studied mutant p53 oncoprotein expression, using PAb1801 monoclonal antibody immunohistochemistry, in 25 'ideal' keratoacanthomas and 26 well-, 19 moderately and 18 poorly differentiated squamous cell carcinomas of the skin. While there was a highly significant trend in the proportion of p53 oncoprotein-positive lesions from keratoacanthomas to poorly differentiated squamous cell carcinomas (chi 2 = 17.13, df = 1, exact P = 0.00003), p53 expression was inadequate for distinguishing keratoacanthoma from well-differentiated squamous cell carcinoma (chi 2 = 2.55, df = 1, exact P = 0.18; corresponding to a sensitivity of 0.84 and a specificity of only 0.36).
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PMID:Mutant p53 oncogene expression in keratoacanthoma and squamous cell carcinoma. 833 63

Many forms of cancer have a higher incidence in relatives of patients than in the general population, and some show Mendelian inheritance. Although individuals genetically predisposed to cancer represent a minority of all cancer patients, the genetic basis for their disease has profound significance. These familial cases provide strong evidence that germline alterations can contribute to cancer. They also provide an ideal opportunity to identify and isolate the genes mutated in common cancers. Products of the tumour suppressor genes have been implicated in several hereditary forms of cancer. The distinct functions of these proteins and their roles in familial cancer will be discussed.
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PMID:The role of tumour suppressor genes in familial cancer. 151 Nov 55

Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.
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PMID:APC mutations occur early during colorectal tumorigenesis. 152 64

The cellular phosphoprotein p53 inhibits progression through the mammalian cell cycle. Both p53 alleles are frequently mutated in human tumours, indicating that p53 is a tumour suppressor. Recent studies have suggested that p53 functions as a transcriptional activator, but the significance of this activity in cell-cycle control has not been established. The adenovirus 2 (Ad2) early 1B (E1B) 55K protein binds to p53 in transformed cells and contributes to oncogenic transformation by Ad2 (refs 10-12). Here we report that mutants of E1B 55K and wild-type Ad12 E1B 54K proteins show a strong correlation between their ability to inhibit p53-mediated transcriptional activation and their ability to cooperate with adenovirus E1A protein in the transformation of primary cells. These results indicate that p53 probably inhibits cell cycling by functioning as a transcription factor.
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PMID:Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. 153 43

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


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