PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence

This article is hosted on a website external to the CBCRA Open Access Archive. Selecting “View/Open” below will launch the full-text article in another browser window.Oncogenic ras activates multiple signaling pathways to enforce cell proliferation in tumor cells. The ERK1/2 mitogen-activated protein kinase pathway is required for the transforming effects of ras, and its activation is often sufficient to convey mitogenic stimulation. However, in some settings oncogenic ras triggers a permanent cell cycle arrest with features of cellular senescence. How the Ras/ERK1/2 pathway activates different cellular programs is not well understood. Here we show that ERK1/2 localize predominantly in the cytoplasm during ras-induced senescence. This cytoplasmic localization seems to be dependent on an active nuclear export mechanism and can be rescued by the viral oncoprotein E1A. Consistent with this hypothesis, we showed that E1A dramatically down-regulated the expression of the ERK1/2 nuclear export factor PEA-15. Also, RNA interference against PEA-15 restored the nuclear localization of phospho-ERK1/2 in Ras-expressing primary murine embryo fibroblasts and stimulated their escape from senescence. Because senescence prevents the transforming effect of oncogenic ras, our results suggest a tumor suppressor function for PEA-15 that operates by means of controlling the localization of phospho-ERK1/2

Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence

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Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase Cδ-dependent Mechanism

Phosphoprotein enriched in astrocytes-15 kDa (PEA-15), a phosphoprotein enriched in astrocytes, inhibits both apoptosis and proliferation in normal and cancerous cells. Here, analysis of PEA-15 expression in glioblastoma organotypic cultures revealed low levels of PEA-15 in tumor cells migrating away from the explants, regardless of the expression levels in the originating explants. Because glioblastomas are highly invasive primary brain tumors that can originate from astrocytes, we explored the involvement of PEA-15 in the control of astrocyte migration. PEA-15−/− astrocytes presented an enhanced motility in vitro compared with their wild-type counterparts. Accordingly, NIH-3T3 cells transfected by green fluorescent protein-PEA-15 displayed a reduced migration. Reexpression of PEA-15 restored PEA-15−/− astrocyte motility to wild-type levels. Pharmacological manipulations excluded a participation of extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt, and calcium/calmodulin-dependent protein kinase II in this effect of PEA-15. In contrast, treatment by bisindolylmaleimide, Gö6976, and rottlerin, and chronic application of phorbol 12-myristate 13-acetate and/or bryostatin-1 indicated that PKCδ mediated PEA-15 inhibition of astrocyte migration. PEA-15−/− astrocytes constitutively expressed a 40-kDa form of PKCδ that was down-regulated upon PEA-15 reexpression. Together, these data reveal a new function for PEA-15 in the inhibitory control of astrocyte motility through a PKCδ-dependent pathway involving the constitutive expression of a catalytic fragment of PKCδ

Philips Oy Healthcaren asiakaspalveluprosessin kehittäminen

Tämän insinöörityön aiheena on parantaa Philips Oy Healthcaren asiakaspalveluprosessia. Työn aiheeseen kuuluu vain pelkästään Suomessa palvelevaa Healthcaren osastoa. Työn tavoitteena oli parantaa Philips Oy Healthcaren asiakaspalveluprosessia työntekijöiden näkökulmasta, koska Philipsin johto näki siinä eniten parannettavaa. Tämän insinöörityön tutkimusmenetelmä oli laadullinen tutkimus, jolloin kaikkia Philips Oy Healthcaren asiakaspalvelijoita haastateltiin sekä myynnin että huollon puolelta. Haastateltavia oli yhteensä kuusi kappaletta ja heitä haastateltiin henkilökohtaisesti. Haastatteluista tehtyjen johtopäätöksien mukaan työtehtävät olivat erittäin epäselkeät. Tämän lisäksi puhelinrinkiin ei saatu sitovuutta ja sähköpostien hoitamisessa oli myös suuria vaikeuksia. Tutkimuksen tulokseksi saatiin uusi prosessikuvaus asiakaspalveluprosessiin, jossa on selitetty eri vaiheet ja tapahtumajärjestykset mahdollisimman selkeästi sekä ratkaisut sähköpostiin ja puhelinrinkiin. Tutkimustulosta eli prosessikuvaus annetaan työntekijöille työtehtävien selkeyttämiseksi, jolloin suurin hyöty aiheutuu työntekijöille työskennellessä