Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 is multifunctional. To assess exactly what function is critical for the prevention of neoplastic transformation has proven difficult. Mutants with substitutions at positions 22 and 23 promised to address the relevance of transcription transactivation since they seemed to be defective specifically for this function. We report here that p53 mutant Q22, S23 [p53 (22,23)] is not only impaired for transactivation but for the repression of the fos promoter and SV40 early promoter. Furthermore, whereas p53 (22,23) fails to efficiently transactivate reporter genes in two p53-negative cell lines, it stimulates reporters and suppresses proliferation in two wild-type (wt) p53-positive cell lines strongly above the levels induced by the transfection procedure alone. This transactivation is refractory to inhibition by MDM-2. Finally, p53 (22,23) expressed from large plasmid quantity (1 microg) is crippled for the mediation of apoptosis in p53-negative Hep3B hepatocarcinoma cells. Nevertheless, at a quantity of only 10 ng, both mutant and wt p53 plasmids but not control plasmid, are able to induce some cell death which is not inhibitable by MDM-2. Thus, a correlation exists between p53's functions to regulate promoters and to efficiently mediate apoptosis in Hep3B cells.
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PMID:p53 transactivation domain mutant Q22, S23 is impaired for repression of promoters and mediation of apoptosis. 866 32

Wild-type (wt) p53 frequently induces apoptosis when expressed in tumor cells whereas mutant p53 acts as an oncoprotein and consequently, stimulates cell proliferation. We report here exceptions to that rule. p53 conformational mutant 175H and DNA contact mutant 273H provoke apoptosis in human p53-deficient Hep3B hepatoma cells with delayed kinetics relative to wt p53. Similarly, c-Myc strongly stimulates apoptosis in these cells. In contrast, viral oncoproteins E1A and E7, and the cellular oncoprotein MDM-2, fail to elicit cytocidal responses. Efficient apoptotic cell death by mutant p53 requires oligomerization as 175H and 273H with deletions between amino acid residues 326 and 347 of the oligomerization domain are nontoxic. Apoptosis by mutant or wt p53 was significantly inhibited by the serine protease inhibitor AEBSF but not by the inactive analog AEBSA. Together, these results suggest that a wt p53-independent control mechanism is operational in Hep3B cells that eliminates cells upon sensing illegitimate proliferation signals originating from certain oncoproteins, including mutant p53 and Myc. We suggest that some tumor cell types lack p53 altogether because they tolerate neither wild-type nor mutant forms of the protein.
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PMID:Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayed kinetics relative to wild-type p53. 1003 Jun 75