Serum and forskolin cooperate to promote G1 progression in Schwann cells by differentially regulating cyclin D1, cyclin E1, and p27(Kip) expression

    Authors

    J. Iacovelli; J. Lopera; M. Bott; E. Baldwin; A. Khaled; N. Uddin;C. Fernandez-Valle

    Comments

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    Abbreviated Journal Title

    Glia

    Keywords

    proliferation; cAMP; erbB2; cell cycle; PI3K; cyclin D1; cyclin E1; krox-20; ERK; DEPENDENT PROTEIN-KINASE; PROLIFERATION; AMP; INHIBITION; GROWTH; SIGNAL; CAMP; MYELINATION; ACTIVATION; HEREGULIN; Neurosciences

    Abstract

    Proliferation of Schwann cells in vitro, unlike most mammalian cells, is not induced by serum alone but additionally requires cAMP elevation and mitogenic stimulation. How these agents cooperate to promote progression through the G1 phase of the cell cycle is unclear. We studied the inte grative effects of these compounds on receptor-mediated signaling pathways and regulators of G1 progression. We show that serum alone induces strong cyclical expression of cyclin D1 and El, 6 and 12 h after addition, respectively. Serum also promotes strong but transient erbB2, ERK, and Akt phosphorylation, but Schwann cells remain arrested in G1 due to high levels of the inhibitor, p27(Kip). Forskolin with serum promotes G1 progression in 22% of Schwann cells between 18 and 24 h by inducing a steady decline in P27(Kip) levels that reaches a nadir at 12 h coinciding with peak cyclin El expression. Forskolin also delays neuregulin-induced loss of erbB2 receptors allowing strong acute activation of PI3K, sustained erbB2 phosphorylation and G1 progression in 31% of Schwann cells. We find that e ability of forskolin to decrease p271(Kip) is associated with its ability to decrease Krox-20 expression that is induced by serum and further increased by neuregulin. Our results explain why serum is required but insufficient to stimulate proliferation and identify two routes by which forskolin promotes proliferation in the presence of serum and neure gulin. These findings provide insights into how G1 progres sion and, cell cycle arrest leading to myelination are regulated in Schwann cells. (C) 2007 Wiley-Liss, Inc.

    Journal Title

    Glia

    Volume

    55

    Issue/Number

    16

    Publication Date

    1-1-2007

    Document Type

    Article

    Language

    English

    First Page

    1638

    Last Page

    1647

    WOS Identifier

    WOS:000250702300003

    ISSN

    0894-1491

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