RESUMO
Defects in neural tube formation are among the most common malformations leading to infant mortality. Although numerous genetic loci appear to contribute to the defects observed in humans and in animal model systems, few of the genes involved have been characterized at the molecular level. Mice lacking the p53 tumour suppressor gene are predisposed to tumours, but the viability of these animals indicates that p53 function is not essential for embryonic development. Here, we demonstrate that a fraction of p53-deficient embryos in fact do not develop normally. These animals display defects in neural tube closure resulting in an overgrowth of neural tissue in the region of the mid-brain, a condition known as exencephaly.
Assuntos
Deleção de Genes , Genes p53 , Defeitos do Tubo Neural/genética , Animais , Apoptose/genética , Sequência de Bases , DNA/análise , Feminino , Masculino , Mesencéfalo/anormalidades , Mesencéfalo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Dados de Sequência Molecular , Defeitos do Tubo Neural/mortalidade , Defeitos do Tubo Neural/patologia , Fenótipo , Fatores SexuaisRESUMO
p53 plays a central role in neuronal cell death resulting from acute injury or disease. To define the pathway by which p53 triggers apoptosis, we used microarray analysis to identify p53 target genes specifically upregulated during apoptosis but not cell cycle arrest. This analysis identified a small subset of targets highly selective for the p53 apoptotic response, including Siva, a proapoptotic protein whose function is not well understood. Siva's expression pattern suggests that it plays an instructive role in apoptosis, and accordingly, we demonstrate that Siva is essential for p53-dependent apoptosis in cerebellar granule neurons. In addition, we determine that endogenous Siva is associated with the plasma membrane and that Caspase-8 and Bid are important for neuronal apoptosis. Our studies highlight the participation of membrane signaling events in p53's apoptotic program in primary neurons and have significant implications for understanding the mechanisms underlying pathogenesis after neuronal injury and in neurodegenerative diseases.
Assuntos
Apoptose/fisiologia , Encefalopatias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Degeneração Neural/genética , Neurônios/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Animais Recém-Nascidos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Caspase 8/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Cerebelo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
The ability of breast cancer cells to resist anoikis, apoptosis caused by detachment of the non-malignant epithelial cells from the extracellular matrix (ECM), is thought to be critical for breast tumor growth, invasion and metastasis. ErbB2, an oncoprotein that is often overproduced in breast tumors, can block breast cancer cell anoikis via mechanisms that are understood only in part. In an effort to understand them better we found that detachment of the non-malignant human breast epithelial cells from the ECM upregulates a protein Perp in these cells. Perp is a component of the desmosomes, multiprotein complexes involved in cell-to-cell adhesion. Perp can cause apoptosis via unknown mechanisms. We demonstrated that Perp upregulation by cell detachment is driven by detachment-induced loss of epidermal growth factor receptor (EGFR). We also found that Perp knockdown by RNA interference (RNAi) rescues detached cells from death which indicates that Perp contributes to their anoikis. We observed that ErbB2, when overexpressed in detached breast epithelial cells, causes Perp downregulation. Furthermore, ErbB2-directed RNAi or treatment with lapatinib, an ErbB2/EGFR small-molecule inhibitor used for breast cancer therapy, upregulated Perp in ErbB2-positive human breast and ovarian carcinoma cells. We established that ErbB2 downregulates Perp by activating an ErbB2 effector protein kinase Mek that blocks detachment-induced EGFR loss in a manner that requires the presence of a signaling protein Sprouty-2. Finally, we observed that restoration of the wild-type Perp levels in ErbB2-overproducing breast epithelial cells increases their anoikis susceptibility and blocks their clonogenicity in the absence of adhesion to the ECM. In summary, we have identified a novel mechanism of ErbB2-mediated mechanism of anoikis resistance of ErbB2-overproducing breast epithelial cells. This mechanism allows such cells to grow without adhesion to the ECM and is driven by ErbB2-induced activation of Mek, subsequent EGFR upregulation and further EGFR-dependent Perp loss.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Receptor ErbB-2/metabolismo , Anoikis/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Genes Supressores de Tumor , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismoRESUMO
The p53 tumor suppressor is a stress sensor, driving cell cycle arrest or apoptosis in response to DNA damage or oncogenic signals. p53 activation by oncogenic signals relies on the p19(Arf) tumor suppressor, while p53 activation downstream of acute DNA damage is reported to be p19(Arf)-independent. Accordingly, p19(Arf)-deficient mouse embryo fibroblasts (MEFs) arrest in response to acute DNA damage. However, p19(Arf) is required for replicative senescence, a condition associated with an activated DNA damage response, as p19(Arf)-/- MEFs do not senesce after serial passage. A possible explanation for these seemingly disparate roles for p19(Arf) is that acute and chronic DNA damage responses are mechanistically distinct. Replicative senescence may result from chronic, low-dose DNA damage responses in which p19(Arf) has a specific role. We therefore examined the role of p19(Arf) in cellular responses to chronic, low-dose DNA-damaging agent treatment by maintaining MEFs in low oxygen and administering 0.5 G y γ-irradiation daily or 150 µM hydroxyurea, a replication stress inducer. In contrast to their response to acute DNA damage, p19(Arf)-/- MEFs exposed to chronic DNA damage do not senesce, revealing a selective role for p19(Arf) in senescence upon low-level, chronic DNA damage. We show further that p53 pathway activation in p19(Arf)-/- MEFs exposed to chronic DNA damage is attenuated relative to wild-type MEFs, suggesting a role for p19(Arf) in fine-tuning p53 activity. However, combined Nutlin3a and chronic DNA-damaging agent treatment is insufficient to promote senescence in p19(Arf)-/- MEFs, suggesting that the role of p19(Arf) in the chronic DNA damage response may be partially p53-independent. These data suggest the importance of p19(Arf) for the cellular response to the low-level DNA damage incurred in culture or upon oncogene expression, providing new insight into how p19(Arf) serves as a tumor suppressor. Moreover, our study helps reconcile reports suggesting crucial roles for both p19(Arf) and DNA damage-signaling pathways in tumor suppression.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Dano ao DNA , Animais , Pontos de Checagem do Ciclo Celular , Raios gama , Genes Supressores de Tumor , Camundongos , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging.
Assuntos
Miogenina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Proteína MyoD/metabolismo , Miogenina/química , Miogenina/genética , Regiões Promotoras Genéticas , Ligação Proteica , Transcrição Gênica , Proteína Supressora de Tumor p53/genéticaAssuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor p53/metabolismo , Senilidade Prematura/genética , Senilidade Prematura/metabolismo , Animais , Apoptose/genética , Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Instabilidade Genômica , Camundongos , Camundongos Knockout , Mutação , Neoplasias/genética , Neoplasias/patologia , Fosforilação , Transdução de Sinais , Proteína Supressora de Tumor p53/genéticaAssuntos
Displasia Ectodérmica/etiologia , Displasia Ectodérmica/metabolismo , Proteínas de Membrana/fisiologia , Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Envelhecimento/patologia , Animais , Suscetibilidade a Doenças , Displasia Ectodérmica/patologia , Epitélio/metabolismo , Epitélio/patologia , Cabelo/anormalidades , Cabelo/metabolismo , Heterozigoto , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Neoplasias/etiologia , Neoplasias/patologia , Fosfoproteínas/genética , Pele/metabolismo , Pele/patologia , Transativadores/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
FoxO transcription factors have a conserved role in longevity, and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the functional interaction between FoxO and p53 have not been fully explored. Here, we show that p53 regulates the expression of FoxO3, one of the four mammalian FoxO genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and thymocytes. We find that p53 transactivates FoxO3 in cells by binding to a site in the second intron of the FoxO3 gene, a genomic region recently found to be associated with extreme longevity in humans. While FoxO3 is not necessary for p53-dependent cell cycle arrest, FoxO3 appears to modulate p53-dependent apoptosis. We also find that FoxO3 loss does not interact with p53 loss for tumor development in vivo, although the tumor spectrum of p53-deficient mice appears to be affected by FoxO3 loss. Our findings indicate that FoxO3 is a p53 target gene, and suggest that FoxO3 and p53 are part of a regulatory transcriptional network that may have an important role during aging and cancer.
Assuntos
Fatores de Transcrição Forkhead/genética , Longevidade/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/genética , Sequência de Bases , Sítios de Ligação , Ciclo Celular/genética , Células Cultivadas , Dano ao DNA , Primers do DNA , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Proteína Forkhead Box O3 , Imidazóis/farmacologia , Camundongos , Piperazinas/farmacologia , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/genética , Regulação para CimaRESUMO
The Drosophila tissue-specific transcription factor NTF-1 provides a useful model system for studying the mechanisms by which promoter-selective factors control the development of a multicellular organism. A number of promoters that may be targets of NTF-1 regulation have been identified. For example, NTF-1 plays a critical role in the tissue-specific expression of the Drosophila Dopa decarboxylase gene. Additionally, by using in vitro assays, it has been possible to characterize the mechanism of NTF-1 activation, revealing its dependence on specific coactivators, or TAFs. Here, we report the use of both in vivo and in vitro assays to identify the functional domains of NTF-1. These consist of an unusually large, unique DNA-binding and dimerization domain, as well as a novel, isoleucine-rich activation domain. This 56-amino-acid activation region fails to interact with the putative Sp1 coactivator, dTAFII110, and thus appears to use a mechanism distinct from the glutamine-rich activation domain of Sp1. Additionally, NTF-1 appears to activate transcription in a species-specific manner, utilizing distinct domains in Drosophila and yeast.
Assuntos
Proteínas de Ligação a DNA/química , Isoleucina/química , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição/química , Sequência de Aminoácidos , Aminoácidos/química , Animais , Células Cultivadas , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Drosophila/embriologia , Proteínas de Drosophila , Proteínas Fúngicas/metabolismo , Dados de Sequência Molecular , Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
The use of mouse models has greatly contributed to our understanding of the role of p53 in tumour suppression. Mice homozygous for a deletion in the p53 gene develop tumours at high frequency, providing essential evidence for the importance of p53 as a tumour suppressor. Additionally, crossing these knockout mice or transgenic expression p53 dominant negative alleles with other tumour-prone mouse strains has allowed the effect of p53 loss on tumour development to be examined further. In a variety of mouse models, absence of p53 facilitates tumorigenesis, thus providing a means to study how the lack of p53 enhances tumour development and to define genetic pathways of p53 action. Depending on the particular model system, loss of p53 either results in deregulated cell-cycle entry or aberrant apoptosis (programmed cell death), confirming results found in cell culture systems and providing insight into in vitro function of p53. Finally, as p53 null mice rapidly develop tumours, they are useful for evaluating agents for either chemopreventative or therapeutic activities.
Assuntos
Genes Supressores de Tumor/genética , Genes p53/genética , Animais , Ciclo Celular/genética , Dano ao DNA/genética , Reparo do DNA/genética , Vírus de DNA Tumorais/genética , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Neoplasias Experimentais/induzido quimicamente , Oncogenes/genéticaRESUMO
The Drosophila melanogaster tissue-specific transcription factor NTF-1 was originally identified in vitro as a protein that could bind to and activate transcription from the Dopa decarboxylase (Ddc) gene. A structure-function analysis of NTF-1 led to the identification of a discrete amino-terminal activation domain. Here, we report that an NTF-1 mutant lacking the activation domain acts as a trans-dominant inhibitor of NTF-1 activation in tissue culture cells by forming inactive heterodimers with the full-length protein. Ectopically expressing this dominant-negative protein or the full-length protein in developing Drosophila embryos leads to dire developmental consequences. Overexpressing the trans-dominant NTF-1 leads to lethality, while overexpressing full-length NTF-1 results in both lethality and morphogenetic defects. Our results suggest that both the activity and the regulation of NTF-1 are critical for viability and proper development of the fly.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Drosophila melanogaster/embriologia , Fatores de Transcrição/fisiologia , Animais , Animais Geneticamente Modificados , Linhagem Celular , Proteínas de Drosophila , Expressão Gênica , Genes Dominantes , Técnicas In Vitro , Larva , Fenótipo , RNA Mensageiro/genéticaRESUMO
In an effort to characterize sequence-specific transcription factors that regulate gene expression during Drosophila development, we identified and purified a novel DNA-binding activity (NTF-1). The purified protein consists of several polypeptides that bind selectively to a functionally important cis-control element of the Ultrabithorax (Ubx) promoter and to the neurogenic elements of both the dopa decarboxylase (Ddc) and fushi tarazu (ftz) promoter/enhancer regions. Purified NTF-1 activates transcription in vitro in a binding site-dependent manner through upstream sequences of the Ubx promoter. A cDNA clone encoding the open reading frame of NTF-1 was isolated, and the deduced primary amino acid sequence of NTF-1 includes a glutamine-rich region reminiscent of the transcriptional activation domains found in Sp1 but no recognizable DNA-binding domain. NTF-1 expression is temporally regulated during embryonic development. In addition, in situ hybridization experiments revealed that NTF-1 is transcribed in a spatially restricted pattern in the embryo, with the highest level of expression observed in the epidermis and a subset of cells in the CNS. Expression of the NTF-1 cDNA in mammalian cells yields a protein that displays DNA-binding and transcriptional activities indistinguishable from that of the collection of proteins isolated from Drosophila embryos. These findings suggest that NTF-1 is a member of a family of developmentally regulated transcription factors that may be involved in directing the expression of genes such as Ubx, Ddc, and ftz in neuronal cells.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Drosophila/genética , Neurônios/metabolismo , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Clonagem Molecular , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/isolamento & purificação , Proteínas de Drosophila , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/isolamento & purificação , Transcrição Gênica , Vaccinia virus/genéticaRESUMO
Mutating the CAACCCCAA sequence in the RNA component of telomerase causes the synthesis in vivo of new telomere sequences corresponding to the mutated RNA sequence, demonstrating that the telomerase contains the template for telomere synthesis. These mutations also lead to nuclear and cell division defects, and senescence, establishing an essential role for telomerase in vivo.
Assuntos
DNA Nucleotidilexotransferase/metabolismo , Mutação , RNA/genética , Tetrahymena/genética , Animais , Sequência de Bases , Expressão Gênica , Genes , Vetores Genéticos , Dados de Sequência Molecular , Plasmídeos , Moldes Genéticos , Tetrahymena/enzimologiaRESUMO
We previously reported that transcriptional regulators can bind selected TAF subunits of the TFIID complex. However, the specificity and function of individual TAFs in mediating transcriptional activation remained unknown. Here we report the in vitro assembly and transcriptional properties of TBP-TAF complexes reconstituted from the nine recombinant subunits of Drosophila TFIID. A minimal complex containing TBP and TAFII250 directs basal but not activator-responsive transcription. By contrast, reconstituted holo-TFIID supports activation by an assortment of activators. The activator NTF-1, which binds TAFII150, stimulates transcription with a complex containing only TBP, TAFII250, and TAFII150, whereas Sp1 binds and additionally requires TAFII110 for activation. Interestingly, TAFII150 enhances Sp1 activation even though this subunit does not bind directly to Sp1. These results establish that specific subcomplexes of TFIID can mediate activation by different classes of activators and suggest that TAFs perform multiple functions during activation.
Assuntos
Proteínas de Drosophila , Proteínas Recombinantes/biossíntese , Fatores Associados à Proteína de Ligação a TATA , Fatores de Transcrição/biossíntese , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Ligação a DNA/metabolismo , Drosophila , Histona Acetiltransferases , Modelos Genéticos , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Ligação Proteica , Fator de Transcrição Sp1/metabolismo , TATA Box , Proteína de Ligação a TATA-Box , Fator de Transcrição TFIID , Transcrição Gênica/fisiologia , Ativação TranscricionalRESUMO
The p53 tumor suppressor limits cellular proliferation by inducing either G1 arrest or apoptosis, depending on the cellular context. To determine if these pathways are mechanistically distinct, we have examined the effects of different p53 mutants in p53 null primary mouse embryo fibroblasts. We chose this system as it is highly physiological and ensures that the interpretation of the results will not be confounded by the presence of endogenous p53 or oncoproteins which target p53. Using single cell microinjection assays for both G1 arrest and apoptosis, with loss-of-function and chimeric gain-of-function mutants, we have demonstrated that transcriptional activation is critical for both processes. Replacement of the p53 activation domain with that of VP16, or replacement of the p53 oligomerization domain with that of GCN4, reconstituted both G1 arrest and apoptosis activities. However, despite the importance of transcriptional activation in both processes, the target gene requirements are different. The p21 cyclin-dependent kinase inhibitor, which has been shown to be a direct target of p53 and a component of the radiation-induced G1 arrest response, is dispensable for oncogene-induced apoptosis, suggesting that these two p53-dependent transcriptional pathways are distinct.
Assuntos
Apoptose , Ciclinas/fisiologia , Oncogenes , Ativação Transcricional , Proteína Supressora de Tumor p53/fisiologia , Proteínas E1A de Adenovirus/biossíntese , Animais , Apoptose/genética , Apoptose/fisiologia , Sítios de Ligação , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ciclinas/genética , Fase G1 , Camundongos , Mutagênese , Transdução de Sinais , Proteína Supressora de Tumor p53/genéticaRESUMO
The retinoblastoma protein, pRB, and the closely related proteins p107 and p130 are important regulators of the mammalian cell cycle. Biochemical and genetic studies have demonstrated overlapping as well as distinct functions for the three proteins in cell cycle control and mouse development. However, the role of the pRB family as a whole in the regulation of cell proliferation, cell death, or cell differentiation is not known. We generated embryonic stem (ES) cells and other cell types mutant for all three genes. Triple knock-out mouse embryonic fibroblasts (TKO MEFs) had a shorter cell cycle than wild-type, single, or double knock-out control cells. TKO cells were resistant to G(1) arrest following DNA damage, despite retaining functional p53 activity. They were also insensitive to G(1) arrest signals following contact inhibition or serum starvation. Finally, TKO MEFs did not undergo senescence in culture and do possess some characteristics of transformed cells. Our results confirm the essential role of the Rb family in the control of the G(1)/S transition, place the three Rb family members downstream of multiple cell cycle control pathways, and further the link between loss of cell cycle control and tumorigenesis.
Assuntos
Proteínas Nucleares/fisiologia , Fosfoproteínas/fisiologia , Proteínas , Proteína do Retinoblastoma/fisiologia , Animais , Ciclo Celular , Divisão Celular , Sobrevivência Celular , Transformação Celular Neoplásica , Células Cultivadas , Meios de Cultura Livres de Soro , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Doxorrubicina/farmacologia , Fase G1 , Marcação de Genes , Genes ras , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteína do Retinoblastoma/genética , Proteína p107 Retinoblastoma-Like , Proteína p130 Retinoblastoma-LikeRESUMO
The p53 tumor suppressor activates either cell cycle arrest or apoptosis in response to cellular stress. Mouse embryo fibroblasts (MEFs) provide a powerful primary cell system to study both p53-dependent pathways. Specifically, in response to DNA damage, MEFs undergo p53-dependent G(1) arrest, whereas MEFs expressing the adenovirus E1A oncoprotein undergo p53-dependent apoptosis. As the p53-dependent apoptosis pathway is not well understood, we sought to identify apoptosis-specific p53 target genes using a subtractive cloning strategy. Here, we describe the characterization of a gene identified in this screen, PERP, which is expressed in a p53-dependent manner and at high levels in apoptotic cells compared with G(1)-arrested cells. PERP induction is linked to p53-dependent apoptosis, including in response to E2F-1-driven hyperproliferation. Furthermore, analysis of the PERP promoter suggests that PERP is directly activated by p53. PERP shows sequence similarity to the PMP-22/gas3 tetraspan membrane protein implicated in hereditary human neuropathies such as Charcot-Marie-Tooth. Like PMP-22/gas3, PERP is a plasma membrane protein, and importantly, its expression causes cell death in fibroblasts. Taken together, these data suggest that PERP is a novel effector of p53-dependent apoptosis.