Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of cell cycle control and acquisition of chromosomal rearrangements such as gene amplification often occur during tumor progression, suggesting that they may be correlated. We show here that the wild-type p53 allele is lost when fibroblasts from patients with the Li-Fraumeni syndrome (LFS) are passaged in vitro. Normal and LFS cells containing wild-type p53 arrested in G1 when challenged with the uridine biosynthesis inhibitor PALA and did not undergo PALA-selected gene amplification. The converse occurred in cells lacking wild-type p53 expression. Expression of wild-type p53 in transformants of immortal and tumor cells containing mutant p53 alleles restored G1 control and reduced the frequency of gene amplification to undetectable levels. These studies reveal that p53 contributes to a metabolically regulated G1 check-point, and they provide a model for understanding how abnormal cell cycle progression leads to the genetic rearrangements involved in tumor progression.
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PMID:Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. 152 30

Transforming growth factor beta 1 (TGF-beta 1) regulates a multitude of diverse biological functions in mammalian cells, and there is good evidence that aberrant expression of this growth factor can play an important role in mechanisms of malignant progression. We show that a TGF-beta 1-overexpressing mouse 10T1/2 cell line transfected with a TGF-beta 1 sequence that allows the synthesis of bioactive growth factor exhibits reduced sensitivity to the cytotoxic effects of the drug N-(phosphonacetyl)-L-aspartate (PALA) in colony-forming experiments. Furthermore, six independent 10T1/2 TGF-beta 1-transfected cell lines containing TGF-beta 1 gene expression under the control of a zinc sulfate-responsive metallothionein promoter were selected. In all cases, sensitivity to PALA cytotoxic effects was significantly reduced when cells were cultured under conditions that led to elevated levels of TGF-beta 1 gene expression when compared to cells containing basal levels of this growth factor. Fluctuation analysis to determine the rate of PALA resistance was performed with several TGF-beta 1-transfected cell lines in which growth factor expression was regulated by the metallothionein promoter. We observed significantly higher rates of PALA resistance/cell/generation in cell populations expressing high levels of TGF-beta 1 than in the same cells expressing relatively low levels of this growth factor. The only mechanism known for PALA resistance in mouse cells involves the amplification of the gene coding for the protein target of PALA, CAD, a multifunctional polypeptide containing carbamyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase. Southern blot analysis of colonies that survived normally cytotoxic concentrations of PALA exhibited CAD gene amplification. In total, these observations indicate that aberrant expression of TGF-beta 1 gene expression decreases the genetic stability of 10T1/2 cells, leading to increased rates of drug resistance and elevated gene amplification potential. The results of this study indicate a new malignancy related function for TGF-beta 1 alterations and suggest a novel role for aberrant expression of this growth factor in mechanisms of drug resistance and tumor progression.
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PMID:Drug resistance and gene amplification potential regulated by transforming growth factor beta 1 gene expression. 771 85

We have investigated the genetic stability of NIH-3T3 cells transfected with sequences coding for basic fibroblast growth factor (bFGF) by determining drug resistance and gene amplification potential. Colony-forming experiments and fluctuation analyses showed that the frequency and rate of resistance to N-(phosphonacetyl)-L-aspartate (PALA) was dramatically elevated in cells transfected with either the normal bFGF coding sequence that lacks a known signal for secretion or a chimeric bFGF sequence that targets the growth factor to the secretory pathway. Basic FGF-transfected cells that grew in the presence of PALA were found to possess an amplification of the CAD gene, which codes for a multifunctional protein involved in pyrimidine biosynthesis and is the site of action for PALA. The observation that these alterations occur in cells transfected with a bFGF sequence, without a conventional signal sequence for secretion, suggests an intracrine as opposed to autocrine mechanism of action. The results describe a new function for this growth factor and suggest a novel role for aberrant expression of bFGF in mechanisms of tumor progression.
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PMID:Aberrant expression of basic fibroblast growth factor in NIH-3T3 cells alters drug resistance and gene amplification potential. 805 Apr 90

Gene amplification accompanies tumor progression and is involved in the development of drug resistance. Previously, we reported (A. Albor et al., Cancer Res. 58: 2091-2094, 1998) that mutant p53 proteins conserve the capacity to interact with and activate topoisomerase I, and that this could be a mechanism for induction of genomic instability by mutant p53 proteins. To test this hypothesis, the effect of exogenous mutant p53 protein expression on genomic instability in human p53-/- Saos-2 cells was measured by the frequency of formation of N-(phosphoacetyl)-L-aspartate (PALA)-resistant (PALA(R)) colonies, mediated by gene amplification. Interaction of exogenous mutant p53 and topoisomerase I was confirmed by immunoprecipitation. Growth under continuous expression of mutant p53 proteins for 16-17 population doublings increased the frequency of appearance of PALA(R) colonies after subsequent exposure to PALA. Subtoxic concentrations of camptothecin (which stabilizes topoisomerase I cleavage complexes, mediating nonhomologous recombination) produced a dose-dependent increase in PALA(R) colonies, and combining expression of mutant p53 with exposure to camptothecin produced a greater than additive increase in PALA(R) colony formation. These results indicate that mutant p53 proteins promote gene amplification independently of their capacity to inactivate the wild-type p53 protein, and suggest that this effect is dependent on interaction of mutant p53 with topoisomerase I. Additional studies are needed to assess the potential of targeting mutant p53 interaction with topoisomerase I for the reduction of drug resistance development during chemotherapy.
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PMID:Induction of gene amplification as a gain-of-function phenotype of mutant p53 proteins. 1203 43