Abstract
Inactivation of p53 is one of the most relevant events in human cancer, since it allows transformed cells to escape their own proliferation control and leave them irresponsive to drugs that aim to damage their DNA. When p53 falls, other members of its family may become targets to attack tumoural cells. p73 has shown capacity to mediate these attacks. However, its N-terminal truncated isoforms have been associated with oncogenesis due to their capacity to act as dominant negatives of p53 and the transactivation (TA) isoforms of p73. We previously found a relationship between the overexpression of N-terminus-truncated p73 isoform (∆Np73) and that of the proapoptotic gene Bcl-2-interacting killer (BIK). In the present report we demonstrate that ∆Np73-α has the capacity to induce apoptosis through the co-ordinated activation of a group of genes harbouring GC-rich elements in their regulatory regions. ∆Np73-α synergizes with specificity protein (Sp1) on these elements but the overall response of these genes probably depends on the additional presence of consensus p53 elements. We explore the domains of ∆Np73-α involved in this transactivation capacity and found divergences with the previously described functions for them. Moreover, we found that the transforming mutation V12 of HRas impairs this transactivation capacity of ∆Np73-α, further supporting the anti-tumoural function of this later. Our data add complexity to the action of p73 on the induction of apoptosis and tumourogenesis, opening new interpretations to the expression profile of p73 isoforms in different human neoplasias.
Highlights
The p53 family of transcription factors are long known for its function in the preservation of the genomic information, activating genes involved in the repair of the DNA, and stopping proliferation and inducing a controlled cell death when the damage exceeds a certain threshold
We found that the increased p53 stabilization in cell lines derived from Fanconi anaemia (FA) patients is paralleled by a N-terminus-truncated p73 isoform (Np73) transcriptional activation [10], so we wanted to explore the functional relationship between these two proteins in the induction of apoptosis in these cells
Once we demonstrated that Np73 is able to activate Bcl-2-interacting killer (BIK) transcription through specificity protein 1 (Sp1) responsive elements, we investigated whether other cell cycle-arresting or apoptosis-promoting genes may be co-ordinately regulated by this isoform
Summary
The p53 family of transcription factors are long known for its function in the preservation of the genomic information, activating genes involved in the repair of the DNA, and stopping proliferation and inducing a controlled cell death when the damage exceeds a certain threshold. Mutations in p53 have been described for virtually all human tumours, making them scape their own control systems and making inefficient all the therapeutic efforts aimed to promote these later This is the main attractive of other members of the p53 family that could mediate a chemotherapy response in the absence of a functional p53. Alternative usage of the exons coding for the C-terminus of the protein produce at least seven variants termed with Greek letters (α–η) Those exons code for a sterile α motif (SAM) domain and a repressive domain located at that end of the protein [2].
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