Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:EXPT01586 (G418)
 2,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The INK4a gene, one of the most frequently disrupted loci in human cancer, encodes two unrelated proteins, p16INK4a and p19ARF, that both block cell proliferation. p16INK4a is a component of the Rb regulatory pathway, while p19ARF has been functionally related to p53. Moreover, p16INK4a is inactivated in many human tumors, while it has been very recently reported that p19ARF null mice develop tumors early in life. We show here that p19ARF is able to inhibit the formation of G418-resistant colonies when transfected into human and mouse cell lines expressing wild-type p53, regardless of p16 status. Moreover its amino terminal domain encoded by exon 1beta is still sufficient to obtain the same effect. We have analysed the ability of p19ARF to interfere with Ras-mediated cellular transformation in the NIH3T3 cell line. Cotransfection of p19ARF together with activated ras potently inhibited the formation of transformed foci in a dose-dependent manner. We have also isolated stable NIH3T3 transfectants expressing p19ARF and we have measured their growth properties as well as their efficiency of transformation by activated ras. Our results suggest that p19ARF can interfere with oncogene-mediated transformation, without significantly affecting NIH3T3 cell growth, at least at the levels of expression achieved in these experiments.
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PMID:Suppression of Ras-mediated NIH3T3 transformation by p19ARF does not involve alterations of cell growth properties. 1032 41

INK4a/ARF locus distinguishes itself by its unusual structure and function. It contains 2 overlapping genes with exons 1 alpha, 2 and 3 encoding p16INK4a and exons 1 beta, 2 and 3 encoding p19ARF. Mice with their exons 2 and 3 of the INK4a/ARF knocked out are viable and fertile but develop spontaneous tumors at an early age and highly sensitive to carcinogenic treatment. However, mice with their exon 1 beta knocked out, without interference the expression of p16INK4a, show almost the same phenotype as those with their exons 2 and 3 knocked out. This raises a question of whether the mouse p16INK4a plays a role in tumor suppression. To investigate this problem, a targeting vector pointing to p16INK4a exon 1 alpha with 1.5 kb Eco81 I/Acc II fragment as short arm and 5.9 kb Xba I/Xho I fragment as long arm was built. After linearlization and purification, the targeting vector was introduced into ES cells through electroporation. Thirty-seven G418- and gancyclovir-resistant colonies were picked out and one of them was confirmed as positive by Southern hybridization.
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PMID:[p16INK4a exon 1 alpha knockout in mouse embryonic stem cells]. 1183 70