p73, a member of the p53 tumor suppressor family, is involved in the DNA damage response and serves as a mediator of p53 tumor suppression. Like p53, p73 is a sequence-specific DNA-binding transcription factor and an important regulator in the control of the cell cycle and apoptosis, p73 is expressed as three major variants, TA, DN, and DTA. The TA variant is transcribed from the upstream promoter and produces at least seven alternatively spliced TA isoforms (p73a-h), which differ in their carboxyl termini. The DN variant is transcribed from an alternate promoter in intron 3 and similarly produces at least another seven alternatively spliced DN isoforms (DNp73a-h). Since the N-terminal activation domain is absent in the DN variant, it is hypothesized that the DN variant is transcriptionally inactive and potentially dominant negative over the TA variant and possibly over p53. Interestingly, we have found and, later several other groups have confirmed, that the DN variant of the p53 family member p63, which also lacks the N-terminal activation domain, is transcriptionally active and capable of inducing specific target genes. Thus, we hypothesize that DNp73 is transcriptionally active and exerts its function by regulating specific target genes. Since p73 is 63% identical in amino acid to p53 in the DNA-binding domain, it can regulate some p53 target genes, presumably via the p53 responsive element. However, we found that the functional domains in p73 are different from that in p53. We also found that while p73 regulates IGFBP3 and GADD45, it does not regulates a luciferase reporter under the control of the p53 responsive element found in both genes. Thus, we hypothesize that p73 regulates some target genes through its unique responsive element. These hypotheses will be addressed in three aims: (1) to analyze the activity of the DN variant of p73, (2) to determine the mechanism by which various p73 isoforms differentially regulate IGFBP3 and GADD45, and (3) to determine the role of IGFBP3 and GADD45 in mediating p73 function.
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