Protein phosphatase 2A is a critical regulator of protein kinase C zeta signaling targeted by SV40 smallt to promote cell growth and NF-kappa B activation

Abstract

of several cell types by SV40, especially when assayed Alphonse Garcia 3 in growth-arrested cells (Martin et al., 1979). Small t also Small t also activates AP-1 in microinjected CV-1 cells in a MAP kinase-dependent fashion (Frost et al., 1994). We have reported that inhibition of protein phosphatHowever, the mechanisms supporting the role of small t ase 2A (PP2A) by expression of SV40 small t stimulates during SV40 infection are far from being completely the mitogenic MAP kinase cascade. Here, we show that understood. SV40 small t can substitute for tumor necrosis factor-αLike PP2A, the atypical calcium-independent protein (TNF-α) or serum and stimulate atypical protein kinase kinase C ζ isoform (PKC ζ) has been involved in the C ζ (PKC ζ) activity, resulting in MEK activation, cell control of mitogenic signal transduction and survival proliferation and NF-κB-dependent gene transcrip- (Berra et al., 1993(Berra et al., , 1995Gomez et al., 1995; Diaz-Meco tional activation in CV-1 and NIH 3T3 cells. Kieser et al., 1996;Powell et al., 1996). PKC effects were abrogated by co-expression of kinase-ζ also plays a pivotal role in tumor necrosis factor-α deficient PKC ζ and inhibition of phosphatidylinositol (TNF-α) activation of NF-κB (Diaz-Meco et al., 1993, 3-kinase p85α-p110 by wortmannin, LY294002 and 1994; Dominguez et al., 1993;Lozano et al., 1994), an a dominant-negative mutant of p85α. In contrast, inducible transcriptional activator that participates in the expression of kinase-inactive ERK2 inhibited small control of cell proliferation and survival, as well as in t-dependent cell growth but was unable to abolish inflammatory response and viral gene expression small t-induced NF-κB transactivation. Our results (reviewed in Bauerle and Baltimore, 1996). NF-κB has provide the first in vivo evidence for a critical regulatory been especially implicated in the transcriptional activation role of PP2A in bifunctional PKC ζ signaling pathways of the human immunodeficiency virus type 1 (HIV-1) long controlled by phosphatidylinositol 3-kinase. Constituterminal repeat (LTR) (reviewed in Gaynor, 1992). NF-κB tive activation of PKC ζ and NF-κB following inhibition is the prototype of a family of heterodimeric transcription of PP2A supports new mechanisms by which SV40 factors composed of monomers that bind to DNA and the small t promotes cell growth and transformation. By I-κB inhibitors (reviewed in Baldwin, 1996). NF-κB is establishing PP2A as a key player in the response of retained in the cytoplasm in its inactive form by the I-κB cells to growth factors and stress signals like TNF-α, α inhibitor. Upon stimulation of cells, I-κB α becomes our findings could explain why PP2A is a primary phosphorylated and dissociates from NF-κB, resulting in target utilized during SV40 infection to alter cellular the translocation of NF-κB to the nucleus, where it carries behavior.out its transactivation function. The rapid phosphorylation Keywords: NF-κB/PI 3-kinase/PKC ζ/PP2A/SV40 of I-κB α represents a possible signal for its proteo...

Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

“…The cell type specific differences in the ability of parthenolide to inhibit constitutive NF-kB could be related to mechanisms of constitutive NF-kB activation in these cells. While autocrine action of interleukin 1 alpha and epidermal growth factor receptor pathway are responsible for constitutive NFkB activation in MDA-MB-231 and MDA-MB-436 cells, SV40 t antigen may be responsible for NF-kB activation in HBL-100 cells (Vanhamme and Szpirer, 1988;Sontag et al, 1997;Biswas et al, 2000;Nozaki et al, 2000). Nonetheless, our results indicate that parthenolide inhibits cell proliferation independent of NF-kB inhibition and the levels of constitutive NF-kB determine the concentration of parthenolide required to inhibit cell proliferation.…”

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…Host cell proliferation can be blocked by pharmacological inhibition of PI3-K In many different systems, PI3-K activity has been linked to proliferative pathways via activation of MAP kinase (Karnitz et al, 1995), p70S6K (Alessi et al, 1997), c-Jun N-terminal kinase (JNK) (Klippel et al, 1996), PKB or proteins of the PKC family (Akimoto et al, 1996;Sontag et al, 1997). To examine whether the continuous proliferation of T. parva-infected B cells depends on PI3-K activity, we took advantage of two unrelated PI3-K inhibitors, LY294002 and wortmannin.…”

G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia

“…Considered together with previous data (Kawabe et al, 1997;Shen et al, 2001), perhaps what is most notable about the current findings is that the oncogenic action of HOX11 is remarkably analogous to that of transforming viral proteins. For example, SV40 large T antigen and adenovirus E1A oncoprotein form complexes with Rb and CBP/p300 (Eckner et al, 1996;Ait-Si-Ali et al, 1998), whereas SV40 small t antigen and polyoma virus small and middle T antigens form complexes with PP2A (Pallas et al, 1990;Sontag et al, 1997). In this regard, a critical role for PP2A in human cell transformation has recently come to light .…”