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Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis
Y Lin1, W Ma, S Benchimol
1Ontario Cancer Institute/Princess Margaret Hospital and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract:
The p53 tumour suppressor promotes cell-cycle arrest or apoptosis in response to cellular stress, such as DNA damage and oncogenesis. This role of p53 is important for its tumour-suppression function and depends, at least in part, on its ability to bind to specific DNA sequences and activate the transcription of target genes. The pathway through which p53 promotes apoptosis is not fully understood. Here we describe a new gene regulated by p53 that encodes a predicted protein of 915 amino acids in mice (910 amino acids in humans), which we have named Pidd. The mouse Pidd cDNA contains a p53 consensus DNA binding sequence upstream of the Pidd-coding region. This sequence element bound to p53 and conferred p53-dependent inducibility on a heterologous reporter gene. Moreover, Pidd RNA was induced by ionizing radiation in a p53-dependent manner and the basal level of Pidd RNA was dependent on Trp53 status. Overexpression of Pidd inhibited cell growth in a p53-like manner by inducing apoptosis. Antisense inhibition of Pidd expression attenuated p53-mediated apoptosis. Our data suggest that Pidd is an effector of p53-dependent apoptosis.
Insights
Researchers discovered a new gene, Pidd, regulated by the p53 tumor suppressor. Pidd acts as an effector, mediating p53-dependent apoptosis and inhibiting cell growth, crucial for tumor suppression.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The p53 tumor suppressor is vital for preventing cancer by inducing cell-cycle arrest or apoptosis in response to cellular stress.
- p53's tumor-suppressive function relies on binding DNA and activating target gene transcription.
- The precise mechanisms by which p53 induces apoptosis are not fully elucidated.
Purpose of the Study:
- To identify and characterize novel genes regulated by p53 involved in apoptosis.
- To investigate the role of a newly identified gene, Pidd, in the p53-mediated apoptotic pathway.
Main Methods:
- Analysis of mouse Pidd cDNA for p53 consensus DNA binding sequences.
- Reporter gene assays to assess p53-dependent inducibility.
- RNA induction studies following ionizing radiation exposure.
- Investigation of Pidd expression levels in relation to Trp53 status.
- Functional studies involving Pidd overexpression and antisense inhibition to assess effects on cell growth and apoptosis.
Main Results:
- A novel gene, Pidd, encoding a predicted protein of 915 amino acids (mouse) or 910 amino acids (human), was identified and found to be regulated by p53.
- The mouse Pidd cDNA contains a functional p53 binding site, conferring p53-dependent inducibility.
- Pidd RNA levels were induced by ionizing radiation in a p53-dependent manner and correlated with Trp53 status.
- Overexpression of Pidd inhibited cell growth by inducing apoptosis, mimicking p53's effects.
- Antisense inhibition of Pidd expression attenuated p53-mediated apoptosis.
Conclusions:
- Pidd is a novel gene directly regulated by the p53 tumor suppressor.
- Pidd functions as an effector molecule in the p53-dependent apoptosis pathway.
- Pidd plays a significant role in mediating the tumor-suppressive functions of p53, particularly in apoptosis induction.