PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D.

The small GTPase H-Ras is a proto-oncogene that activates a variety of different pathways including the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway. H-Ras is mutated in many human malignancies, and these mutations cause the protein to be constitutively active. Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) blocks ERK-dependent gene transcription and inhibits proliferation by sequestering ERK in the cytoplasm. We therefore investigated whether PEA-15 influences H-Ras-mediated transformation. We found that PEA-15 does not block H-Ras-activated proliferation when H-Ras is constitutively active. We show instead that in H-Ras-transformed mouse kidney epithelial cells, co-expression of PEA-15 resulted in enhanced soft agar colony growth and increased tumor growth in vivo. Overexpression of both H-Ras and PEA-15 resulted in accelerated G1/S cell cycle transition and increased activation of the ERK signaling pathway. PEA-15 mediated these effects through activation of its binding partner phospholipase D1 (PLD1). Inhibition of PLD1 or interference with PEA-15/PLD1 binding blocked PEA-15's ability to increase ERK activation. Our findings reveal a novel mechanism by which PEA-15 positively regulates Ras/ERK signaling and increases the proliferation of H-Ras-transformed epithelial cells through enhanced PLD1 expression and activation. Thus, our work provides a surprising mechanism by which PEA-15 augments H-Ras-driven transformation. These data reveal that PEA-15 not only suppresses ERK signaling and tumorigenesis but also alternatively enhances tumorigenesis in the context of active Ras.

Frequency of post-poisoning exposure information provided to patients requiring emergency care.

Pediatric unintentional poisoning is common despite preventative efforts. Children who have had a poison exposure are at increased risk for subsequent exposure. The purpose of our trial was to determine how often poison prevention information is provided to child care providers in health care facilities (HCF). This was a prospective telephone survey of 100 cases of unintentional poisonings of children ages 1-5 y referred to a HCF. Excluded were cases of patients that had intentional or chronic exposures. Eighty cases received no prevention material; 20 cases received Poison Prevention Information. Ninety-three of the patients were discharged from the emergency department, 6 patients were discharged from a pediatric floor, and 1 was discharged from a Pediatric ICU. Follow up calls to home may be difficult after the patient is referred to a HCF and many families did not receive poison prevention materials. This study indicates the need for a poison prevention discharge packet to be distributed to provide uniform and complete poison prevention education.