In a screen to identify genes activated during p53-mediated apoptosis but not G1 arrest, we previously isolated a novel gene known as Perp (P53 apoptosis Effector Related to PMP-22). Perp induction correlates with p53-dependent apoptosis and not p53-independent cell death, and Perp overexpression can induce cell death in p53-deficient MEFs. We subsequently demonstrated that the requirement for Perp in p53-dependent apoptosis is dependent on the cellular context - while the absence of Perp partially compromises apoptosis in immature thymocytes and neurons, Perp is dispensable for apoptosis in E1A-MEFs.
In addition to its role in apoptosis, analysis of the Perp knockout mouse revealed a second unexpected role for this protein in cell-cell adhesion. In the absence of DNA damage, Perp is expressed in the developing and mature stratified epithelia, and endogenous Perp protein localizes to the desmosome, a multiprotein complex required for normal cell-cell adhesion in these tissues. Perp null mice die within the first week of life, as a result of severe adhesion defects and blistering in the skin and oral mucosa, and exhibit highly abnormal desmosomes by electron microscopy. This essential role in adhesion appears to be p53-independent; rather, developmental expression of Perp is regulated by the related transcription factor p63, a master regulator of epithelial development.
The dual roles of Perp in adhesion and apoptosis argue strongly that this protein may be affected in diverse human diseases. Mutations in p63 underlie multiple human developmental disorders affecting the stratified epithelia. In addition, every identified desmosomal protein has been shown to be affected in one or more human blistering diseases affecting the skin, hair, or oral mucosa. Perp may therefore be mutated in blistering diseases of unknown genetic origin. Finally, emerging work from other labs on the roles of p53 family members p63 and p73 in tumor suppression suggests that loss of p63 may affect tumor spectrum and metastasis. Perp, as a gene that can be transactivated by p53 and p63 to affect both adhesion and apoptosis, may be an important part of the pathways preventing tumor progression and invasion.
We are currently characterizing Perp and its encoded protein using genetic, cell biological, and biochemical techniques. We are constructing a Perp conditional knockout mouse to further define the function of Perp in development and tumorigenesis. We are also dissecting the mechanisms by which Perp induces cell death and cell adhesion. Perp is a multipass transmembrane protein that could act either as a signalling molecule or as an ion channel. The generation and analysis of Perp mutants will be helpful for determining how Perp exerts its effects on known steps of the apoptotic process, thus defining a link between p53 and the execution of apoptosis.
Perp protein is expressed in stratified epithelia, including the skin and hair follicle, where it plays a key role in desmosomal cell-cell adhesion and epithelial integrity.
Northern blot analysis shows that Perp is selectively induced to high levels during p53-dependent apoptosis compared to cell cycle arrest. This is in contrast to classical p53 target genes, and therefore Perp may be involved in dictating the apoptotic cell fate.
In situ hybridization showing Perp expression in a variety of epithelia during development.
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