The contribution of transactivation subdomains 1 and 2 to p53-induced gene expression is heterogeneous but not subdomain-specific.
Two adjacent regions within the transactivation domain of p53 are sufficient to support sequence-specific transactivation when fused to a heterologous DNA binding domain. It has been hypothesized that these two subdomains of p53 may contribute to the expression of distinct p53-responsive genes. Here we have used oligonucleotide microarrays to identify transcripts induced by variants of p53 with point mutations within subdomains 1, 2, or 1 and 2 (QS1, QS2, and QS1/QS2, respectively). The expression of 254 transcripts was increased in response to wild-type p53 expression but most of these transcripts were poorly induced by these variants of p53. Strikingly, a number of known p53-regulated transcripts including TNFRSF10B, BAX, BTG2, and POLH were increased to wild-type levels by p53(QS1) and p53(QS2) but not p53(QS1/QS2), indicating that either subdomain 1 or 2 is sufficient for p53-dependent expression of a small subset of p53-responsive genes. Unexpectedly, there was no evidence for p53(QS1)- or p53(QS2)-specific gene expression. Taken together, we found heterogeneity in the requirement for transactivation subdomains 1 and 2 of p53 without any subdomain-specific contribution to p53-induced gene expression.
Smith
Jennifer M
JM
Cancer Therapeutics Program, Ottawa Health Research Institute, 501 Smyth Rd, Ottawa, ON, Canada K1H 8L6.
Stubbert
Lawton J
LJ
Hamill
Jeffrey D
JD
McKay
Bruce C
BC
D000230:Adenocarcinoma / Q000473:pathology; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics*; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000172:deficiency / Q000502:physiology
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53