RESUMEN
Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs-2 diandric triploid and 1 triandric tetraploid-and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum ß-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Mola Hidatiforme/química , Neoplasias Uterinas/química , Adulto , Biomarcadores de Tumor/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Humanos , Mola Hidatiforme/genética , Mola Hidatiforme/patología , Inmunohistoquímica , Técnicas de Diagnóstico Molecular , Sobrediagnóstico , Valor Predictivo de las Pruebas , Embarazo , Pronóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Adulto JovenRESUMEN
Fetal hepatic stem/progenitor cells, hepatoblasts, are highly proliferative cells and the source of both hepatocytes and cholangiocytes. In contrast, mature hepatocytes have a low proliferative potency and high metabolic functions. Cell proliferation is regulated by cell cycle-related molecules. However, the correlation between cell cycle regulation and hepatic maturation are still unknown. To address this issue, we revealed that the cell cycle inhibitor p57(Kip2) was expressed in the hepatoblasts and mesenchymal cells of fetal liver in a spatiotemporal manner. In addition, we found that hepatoblasts in p57(Kip2)-/- mice were highly proliferative and had deficient maturation compared with those in wild-type (WT) mice. However, there were no remarkable differences in the expression levels of cell cycle- and bipotency-related genes except for Ccnd2. Furthermore, p57(Kip2)-/- hepatoblasts could differentiate into mature hepatocytes in p57(Kip2)-/- and WT chimeric mice, suggesting that the intrinsic activity of p57(Kip2) does not simply regulate hepatoblast maturation.
Asunto(s)
Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Hepatocitos/metabolismo , Hígado/embriología , Hígado/metabolismo , Animales , Ciclo Celular/genética , Diferenciación Celular/genética , Proliferación Celular , Quimera , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Epitelio/embriología , Epitelio/metabolismo , Espacio Extracelular/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hepatocitos/citología , Hígado/citología , Ratones Endogámicos C57BL , Factores de Transcripción/metabolismoRESUMEN
Successful regeneration of injured peripheral nerves is mainly attributed to the plastic behavior of Schwann cells. Upon loss of axons, these cells trans-differentiate into regeneration promoting repair cells which provide trophic support to regrowing axons. Among others, activation of cJun was revealed to be involved in this process, initiating the stereotypic pattern of Schwann cell phenotype alterations during Wallerian degeneration. Nevertheless, the ability of Schwann cells to adapt and therefore the nerve's potential to regenerate can be limited in particular after long term denervation or in neuropathies leading to incomplete regeneration only and thus emphasizing the need for novel therapeutic approaches. Here we stimulated primary neonatal and adult rat Schwann cells with Fingolimod/FTY720P and investigated its impact on the regeneration promoting phenotype. FTY720P activated a number of de-differentiation markers including cJun and interfered with maturation marker and myelin expression. Functionally, FTY720P treated Schwann cells upregulated growth factor expression and these cells enhanced dorsal root ganglion neurite outgrowth on inhibitory substrates. Our results therefore provide strong evidence that FTY720P application supports the generation of a repair promoting cellular phenotype and suggest that Fingolimod could be used as treatment for peripheral nerve injuries and diseases.
Asunto(s)
Clorhidrato de Fingolimod/farmacología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Inmunosupresores/farmacología , Regeneración Nerviosa/efectos de los fármacos , Células de Schwann/efectos de los fármacos , Células de Schwann/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , AMP Cíclico/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Embrión de Mamíferos , Ganglios Espinales/citología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratas , Ratas Wistar , Células de Schwann/química , Transducción de Señal/efectos de los fármacosRESUMEN
T cells are key components of the immune system, playing a central role in cell-mediated immunity. The sequential differentiation of T cells is associated with strict regulation of the cell cycle at each developmental stage. A balance between p53 activity and pre-T cell receptor (TCR) signaling regulates proliferation and differentiation decisions made by these cells. The relation between maintenance of this balance and the function of cell cycle regulators has remained largely unknown, however. We now show that mice with T cell-specific deficiency of the cyclin-dependent kinase inhibitor p57 manifest a differentiation block at the early stage of T cell maturation. Further genetic analysis showed that this defect is attributable to an imbalance between p53 activity and pre-TCR signaling caused by hyperactivation of the E2F-p53 pathway. Moreover, ablation of both p57 and p53 in T cells led to the development of aggressive thymic lymphomas with a reduced latency compared with that apparent for p53-deficient mice, whereas ablation of p57 alone did not confer susceptibility to this hematologic malignancy. Our results thus show that the p57-E2F-p53 axis plays a pivotal role in the proper development of T cells as well as in the prevention of lymphomagenesis.
Asunto(s)
Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Linfoma/genética , Linfoma/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/genética , Diferenciación Celular/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Femenino , Heterocigoto , Linfoma/mortalidad , Linfoma/patología , Ratones , Ratones Noqueados , Fenotipo , Fosforilación , Proteína de Retinoblastoma/metabolismo , Linfocitos T/citología , Linfocitos T/metabolismo , Linfocitos T/patología , Timo/metabolismo , Timo/patologíaRESUMEN
Imprinted genes have been implicated in early embryonic, placental, and neonatal development and alterations in expression levels of these genes can lead to growth abnormalities and embryonic lethality. However, little is known about the functions of bovine imprinted genes during the pre-implantation period. Therefore, the objective of this study was to assess the influence of altered expression of imprinted genes on developmental progress of embryos using small interfering RNA (siRNA). Expression levels of 18 imprinted genes (MAGEL2, UBE3A, IGF2R, NAP1L5, TSSC4, PEG3, NDN, CDKN1C, PHLDA2, MKRN3, USP29, NNAT, PEG10, RTL1, IGF2, H19, MIM1, and XIST) were compared between embryos reaching the blastocyst stage and growth-arrested embryos (degenerates) using quantitative real-time PCR (qRT-PCR). Ten genes were found to be differentially expressed between blastocysts and degenerates. The CDKN1C gene showed the highest upregulation in blastocysts whereas PHLDA2 was highly expressed in degenerates. To assess whether the observed differential gene expression was causative or resultant of embryo degeneration, these genes were selected for functional analysis using siRNA. Injection of siRNA specific to PHLDA2 into one-cell zygotes resulted in a substantial increase in blastocyst development, whereas injection of CDKN1C-specific siRNA resulted in a 45% reduction (Pâ=â0.0006) in blastocyst development. RNA-Seq analysis of CDKN1C-siRNA-injected vs. non-injected embryos revealed 51 differentially expressed genes with functions in apoptosis, lipid metabolism, differentiation, and cell cycle regulation. Gene ontology analysis revealed nine pathways related to cell signaling, metabolism, and nucleic acid processing. Overall, our results show that proper expression levels of the imprinted genes CDKN1C and PHLDA2 are critical for embryo development, which suggests that these genes can be used as markers for normal blastocyst formation.
Asunto(s)
Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Implantación del Embrión/genética , Técnicas de Silenciamiento del Gen , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Animales , Bovinos , ARN Interferente Pequeño/genética , TranscriptomaRESUMEN
p57 and Ras homology A (RhoA) have been implicated in the growth and metastasis of several types of human cancers. This study aimed to detect their expression in hepatocellular carcinoma (HCC) tissue specimens and to determine a possible association with clinicopathological data and patient survival. A total of 80 HCC and corresponding distant normal tissue specimens were processed for immunohistochemical and qPCR analyses of p57 and RhoA expression. The data showed that expression of p57 mRNA and protein was reduced in HCC tissues when compared to that in distant non-cancer tissues (P<0.05), while expression of RhoA mRNA and protein was significantly higher in HCC tissue specimens when compared to that of the distant normal tissues. Loss of p57 expression was associated with HCC with higher α-fetoprotein (AFP) levels (>400 ng/ml; P=0.044), larger tumor size (>5 cm, P=0.004), poor tumor differentiation (P=0.020), advanced TNM stage (P=0.027), capsule invasion (P=0.018) and tumor thrombosis (P=0.008), whereas expression of RhoA protein was signiï¬cantly associated with poor tumor differentiation (P=0.042), capsule invasion (P=0.022), and tumor thrombosis (P=0.002). Furthermore, there was a strong inverse relationship between p57 and RhoA expression in HCC tissues, indicating that loss of p57 expression may contribute to RhoA overexpression in HCC tissues. The median survival time of HCC patients with p57+ and p57- expression was 13.0 and 9.0 months, respectively, whereas the median survival time of HCC patients with RhoA+ and RhoA- was 9.0 and 15.0 months. Univariate analysis revealed that the levels of AFP, tumor size, TNM stage, histological grade, capsule invasion, tumor thrombosis, p57, RhoA and co-expression of p57 and RhoA were all significant prognostic indicators for overall survival of HCC patients. Multivariate analysis showed that tumor size, TNM stage, p57, RhoA and combined loss of p57 with RhoA were risk factors for poor survival of HCC patients. This study indicates that the abnormal expression of p57 and RhoA contributes to progression of HCC and poor survival of patients.
Asunto(s)
Carcinoma Hepatocelular , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Neoplasias Hepáticas , Proteína de Unión al GTP rhoA/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Proliferación Celular , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/genética , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/metabolismo , Sobrevida , Adulto Joven , Proteína de Unión al GTP rhoA/biosíntesisRESUMEN
Distinction of hydatidiform moles (HM) from nonmolar specimens and their subclassification as complete (CHM) versus partial hydatidiform mole (PHM) are important for clinical practice and investigational studies to refine ascertainment of risk of persistent gestational trophoblastic disease (GTD), which differs among these entities. Immunohistochemical analysis of p57 expression, a paternally imprinted maternally expressed gene on 11p15.5, and molecular genotyping are useful for improving diagnosis. CHMs are characterized by androgenetic diploidy, with loss of p57 expression due to lack of maternal DNA. Loss of p57 expression distinguishes CHMs from both PHMs (diandric triploidy) and nonmolar specimens (biparental diploidy), which retain expression. We report a unique HM characterized by morphologic features suggesting an early CHM, including lack of p57 expression by immunohistochemistry, but with genetic features more in keeping with a PHM. Specifically, molecular genotyping by short tandem repeat markers provided evidence to support interpretation as a PHM by demonstrating allele patterns and ratios most consistent with diandric triploidy, with evidence of loss of the maternal copy of chromosome 11 to explain the lack of p57 expression. This case illustrates the value of combined traditional pathologic and ancillary molecular techniques for refined diagnosis of molar specimens. It also raises questions regarding which modalities should be used to ultimately define the subtypes of HMs and whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying risk of persistent GTD.
Asunto(s)
Mola Hidatiforme/diagnóstico , Triploidía , Neoplasias Uterinas/diagnóstico , Adulto , Deleción Cromosómica , Cromosomas Humanos Par 11 , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Diagnóstico Diferencial , Femenino , Humanos , Mola Hidatiforme/clasificación , Mola Hidatiforme/genética , Pelvis/diagnóstico por imagen , Embarazo , Ultrasonografía , Neoplasias Uterinas/genéticaRESUMEN
Mounting evidence indicates cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family, including p57(Kip2) and p27(Kip1), control not only cell cycle exit but also corticogenesis. Nevertheless, distinct activities of p57(Kip2) remain poorly defined. Using in vivo and culture approaches, we show p57(Kip2) overexpression at E14.5-15.5 elicits precursor cell cycle exit, promotes transition from proliferation to neuronal differentiation, and enhances process outgrowth, while opposite effects occur in p57(Kip2)-deficient precursors. Studies at later ages indicate p57(Kip2) overexpression also induces precocious glial differentiation, suggesting stage-dependent effects. In embryonic cortex, p57(Kip2) overexpression advances cell radial migration and alters postnatal laminar positioning. While both CKIs induce differentiation, p57(Kip2) was twice as effective as p27(Kip1) in inducing neuronal differentiation and was not permissive to astrogliogenic effects of ciliary neurotrophic factor, suggesting that the CKIs differentially modulate cell fate decisions. At molecular levels, although highly conserved N-terminal regions of both CKIs elicit cycle withdrawal and differentiation, the C-terminal region of p57(Kip2) alone inhibits in vivo migration. Furthermore, p57(Kip2) effects on neurogenesis and gliogenesis require the N-terminal cyclin/CDK binding/inhibitory domains, while previous p27(Kip1) studies report cell cycle-independent functions. These observations suggest p57(Kip2) coordinates multiple stages of corticogenesis and exhibits distinct and common activities compared with related family member p27(Kip1).
Asunto(s)
Diferenciación Celular/fisiología , Inhibición de Migración Celular/fisiología , Corteza Cerebral/embriología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Células-Madre Neurales/enzimología , Neurogénesis/fisiología , Animales , Células Cultivadas , Corteza Cerebral/citología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/fisiología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Masculino , Ratones , Ratones Noqueados , Células-Madre Neurales/citología , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Although p27 and p57 are structurally related cyclin-dependent kinase inhibitors (CKIs), and are thought to perform similar functions, p27 knockout (p27(KO)) and p57(KO) mice show distinct phenotypes. To elucidate the in vivo functions of these CKIs, we have now generated a knock-in mouse model (p57(p27KI)), in which the p57 gene has been replaced with the p27 gene. The p57(p27KI) mice are viable and appear healthy, with most of the developmental defects characteristic of p57(KO) mice having been corrected by p27 knock-in. Such developmental defects of p57(KO) mice were also ameliorated in mice deficient in both p57 and the transcription factor E2F1, suggesting that loss of p57 promotes E2F1-dependent apoptosis. The developmental defects apparent in a few tissues of p57(KO) mice were unaffected or only partially corrected by knock-in expression of p27. Thus, these observations indicate that p57 and p27 share many characteristics in vivo, but that p57 also performs specific functions not amenable to substitution with p27.
Asunto(s)
Inhibidor p27 de las Quinasas Dependientes de la Ciclina/fisiología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/fisiología , Animales , Apoptosis , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Factor de Transcripción E2F1/deficiencia , Técnicas de Sustitución del Gen , Crecimiento y Desarrollo , Ratones , Ratones Noqueados , FenotipoRESUMEN
Patterning and differentiation signals are often believed to drive the developmental program, including cell cycle exit of proliferating progenitors. Taking advantage of the spatial and temporal separation of proliferating and differentiated cells within the developing anterior pituitary gland, we investigated the control of cell proliferation during organogenesis. Thus, we identified a population of noncycling precursors that are uniquely marked by expression of the cell cycle inhibitor p57(Kip2) and by cyclin E. In p57(Kip2-/-) mice, the developing pituitary is hyperplastic due to accumulation of proliferating progenitors, whereas overexpression of p57(Kip2) leads to hypoplasia. p57(Kip2)-dependent cell cycle exit is not required for differentiation, and conversely, blockade of cell differentiation, as achieved in Tpit(-/-) pituitaries, does not prevent cell cycle exit but rather leads to accumulation of p57(Kip2)-positive precursors. Upon differentiation, p57(Kip2) is replaced by p27(Kip1). Accordingly, proliferating differentiated cells are readily detected in p27(Kip1-/-) pituitaries but not in wild-type or p57(Kip2-/-) pituitaries. Strikingly, all cells of p57(Kip2-/-);p27(Kip1-/-) pituitaries are proliferative. Thus, during normal development, progenitor cell cycle exit is controlled by p57(Kip2) followed by p27(Kip1) in differentiated cells; these sequential actions, taken together with different pituitary outcomes of their loss of function, suggest hierarchical controls of the cell cycle that are independent of differentiation.
Asunto(s)
Ciclo Celular , Diferenciación Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Hipófisis/citología , Células Madre/citología , Animales , Proliferación Celular , Ciclina E/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Proteínas de Homeodominio/metabolismo , Ratones , Ratones Noqueados , Modelos Biológicos , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/metabolismoRESUMEN
The p57(Kip2) gene belongs to the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors and has been suggested to be a tumor suppressor gene, being inactivated in various types of human cancers. However, little is known concerning p57(Kip2) possible interplay with the apoptotic cell death machinery and its possible implication for cancer. Here, we report that selective p57(Kip2) expression sensitizes cancer cells to apoptotic agents such as cisplatin, etoposide and staurosporine (STS) via a mechanism, which does not require p57(Kip2)-mediated inhibition of CDK. Translocation of p57(Kip2) to mitochondria occurs within 20 min after STS application. In fact, p57(Kip2) primarily promotes the intrinsic apoptotic pathways, favoring Bax activation and loss of mitochondrial transmembrane potential, consequent release of cytochrome-c into cytosol, caspase-9 and caspase-3 activation. In accordance, Bcl2 overexpression or voltage-dependent anion channel (VDAC) inhibition is able to inhibit p57(Kip2) cell death promoting effect. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57(Kip2) influences the mitochondrial apoptotic cell death pathway in cancer cells.
Asunto(s)
Apoptosis/fisiología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/fisiología , Animales , Apoptosis/efectos de los fármacos , Transporte Biológico Activo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Células Cultivadas , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Células HeLa , Humanos , Ratones , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Mutación , Estaurosporina/farmacología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Pre-eclampsia affects 6-10% of pregnancies and is one of the primary causes of premature birth. It is widely accepted that inappropriate placental development, combined with environmental factors, plays a major role in disease pathogenesis. The p57(Kip2) mouse is the only mouse model of pre-eclampsia that recapitulates the full spectrum of symptoms of the human disease, including placental abnormalities, hypertension, proteinuria and premature labour. In addition, pregnant females expressing wild-type levels of p57(Kip2) develop pre-eclampsia when carrying fetuses that lack p57(Kip2) expression. This demonstrates that either the fetus or the placenta causes the disease. Here, taking advantage of the unique genetics of the p57(Kip2) mouse, we have used full genome expression profiling to define the placental aspect of the p57(Kip2) phenotype at a molecular level and to conduct an unbiased search for factors involved in pre-eclampsia pathogenesis. During this analysis, we found that although mutant embryos demonstrate altered placental architecture and have histological changes indicative of reduced utero-placental blood flow, the p57(Kip2) pregnant females do not demonstrate hypertension or renal pathology. This suggests a model in which placental abnormalities cause pre-eclampsia only given other environmental variables. On the basis of this model, we expect that misregulation of molecular factors, while not able to cause a full spectrum of disease symptoms in this context, still occurs in these p57(Kip2) mutant mice. Our studies suggest a role for environmental factors in the p57(Kip2) pre-eclampsia phenotype and have identified several candidates for pre-eclampsia predisposition in this model, including known regulators of blood pressure, inflammation and apoptosis.