Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis.

Signal transducer and activator of transcription (STAT) proteins perform key roles in mediating signaling by cytokines and growth factors, including platelet-derived growth factor (PDGF). In addition, Src family kinases activate STAT signaling and are required for PDGF-induced mitogenesis in normal cells. One STAT family member, Stat3, has been shown to have an essential role in cell transformation by the Src oncoprotein. However, the mechanisms by which STAT-signaling pathways contribute to mitogenesis and transformation are not fully defined. We show here that disruption of Stat3 signaling by using dominant-negative Stat3beta protein in NIH 3T3 fibroblasts suppresses c-Myc expression concomitant with inhibition of v-Src-induced transformation. Ectopic expression of c-Myc is able to partially reverse this inhibition, suggesting that c-Myc is a downstream effector of Stat3 signaling in v-Src transformation. Furthermore, c-myc gene knockout fibroblasts are refractory to transformation by v-Src, consistent with a requirement for c-Myc protein in v-Src transformation. In normal NIH 3T3 cells, disruption of Stat3 signaling with dominant-negative Stat3beta protein inhibits PDGF-induced mitogenesis in a manner that is reversed by ectopic c-Myc expression. Moreover, inhibition of Src family kinases with the pharmacologic agent, SU6656, blocks Stat3 activation by PDGF. These findings, combined together, delineate the signaling pathway, PDGF --> Src --> Stat3 --> Myc, that is important in normal PDGF-induced mitogenesis and subverted in Src transformation.

Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling.

While the activated viral Src oncoprotein, v-Src, induces uncontrolled cell growth, the mechanisms underlying cell cycle deregulation by v-Src have not been fully defined. Previous studies demonstrated that v-Src induces constitutively active STAT3 signaling that is required for cell transformation and recent data have implicated STAT3 in the transcriptional control of critical cell cycle regulators. Here we show in mouse fibroblasts stably transformed by v-Src that mRNA and protein levels of p21 (WAF1/CIP1), cyclin D1, and cyclin E are elevated. Using reporter constructs in transient-transfection assays, the cyclin D1 and p21 promoters were both found to be transcriptionaly induced by v-Src in a STAT3-dependent manner. The kinase activities of cyclin D/CDK4, 6 and cyclin E/CDK2 complexes were only slightly elevated, consistent with the findings that coordinate increases in p21, cyclin D1 and cyclin E resulted in an increase in cyclin/CDK/p21 complexes. Similar results were obtained in NIH3T3 and BALB/c 3T3 cells stably transformed by v-Src, indicating that these regulatory events associated with STAT3 signaling represent common mechanisms independent of cell line or clonal variation. These findings suggest that STAT3 has an essential role in the regulation of critical cell cycle components in v-Src transformed mouse fibroblasts.

Feeding dysfunction in infants with severe chronic renal failure after long-term nasogastric tube feeding.

Nasogastric tube feeding (NGTF) is frequently necessary to overcome the inadequate caloric intake of children with severe chronic renal failure (CRF). In a multicenter retrospective study, we evaluated feeding dysfunction after tube feeding withdrawal in children with severe CRF who started long-term enteral nutrition early in childhood. We considered, almost exclusively, infants who had started NGTF very early and continued to be tube fed for at least 9 months. Twelve patients were included in the study: 8 showed significant and persistent eating difficulties, with difficulties in chewing and swallowing in 7 and food refusal in 6. For 2 patients "panic attacks" from swallowing were repeatedly reported. These problems persisted for more than year in 5 patients and between 1 and 6 months in 4. The possible feeding difficulties that may follow NTGF must be carefully evaluated. A possible means of overcoming these difficulties might include: encouraging the use of a pacifier, proposing water for spontaneous assumption, leaving the child the possibility of eating food spontaneously during the daytime, and increased support for the parents during weaning. These need prospective study.

Prenatal ultrasonographic findings of dominant polycystic kidney disease and postnatal renal evolution.

Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common genetic disorder, and its prenatal diagnosis has been reported with increasing frequency. Nevertheless, no data are available on the significance of prenatal ultrasound (US) patterns in predicting postnatal renal function and outcome. We report on one case of ADPKD diagnosed prenatally by US, and on two cases diagnosed immediately after birth, with different prenatal US and renal outcomes. Data on prenatal US findings and postnatal renal evolution are scanty and largely incomplete. Apparently, none of the prenatal findings are consistently different in cases with and without normal postnatal renal function and blood pressure. More complete information on prenatal US findings and postnatal renal evolution is urgently needed.