Down-regulation of p27   by Two Mechanisms, Ubiquitin-mediated Degradation and Proteolytic Processing

Shirane, Michiko; Harumiya, Yumiko; Ishida, Noriko; Hirai, Aizan; Miyamoto, Chikara; Hatakeyama, Susumi; Nakayama, Kei Ichi; Kitagawa, Masatoshi

doi:10.1074/jbc.274.20.13886

Cited by 216 publications

(172 citation statements)

References 46 publications

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“…This 24 kDa protein may be Effects of SHIP on signal transduction and proliferation S Horn et al identical to the N-terminal truncated form of p27 Kip1 which is generated after removal of the cyclin-binding domain at the Nterminus of p27 Kip1 . 42 The increased stability of p27 Kip1 after induction of SHIP expression resulted in an 1.8-and 1.6-fold increase of the steady-state levels of p27 Kip1 in the Jurkat-SHIP clones #39 and #51, respectively (Figure 6c). These results indicate that the expression of SHIP affects two important cell cycle regulators of the G1 phase of the cell cycle, that is, Kip1 and Rb.…”

Section: Induced Expression Of Ship Affects the G1 Cell Cycle Regulatmentioning

confidence: 99%

Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle

et al. 2004

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The inositol 5-phosphatase SHIP (SHIP-1) is a negative regulator of signal transduction in hematopoietic cells and targeted disruption of SHIP in mice leads to a myeloproliferative disorder. We analyzed the effects of SHIP on the human leukemia cell line Jurkat in which expression of endogenous SHIP protein is not detectable. Restoration of SHIP expression in Jurkat cells with an inducible expression system caused a 69% reduction of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) and a 65% reduction of Akt kinase activity, which was associated with reduced phosphorylation of glycogen synthase kinase 3b (GSK-3b) (Ser-9) without changing the phosphorylation of Bad (Ser-136), FKHR (Ser-256) or MAPK (Thr-202/Tyr-204). SHIP-expressing Jurkat cells showed an increased transit time through the G1 phase of the cell cycle, but SHIP did not cause a complete cell cycle arrest or apoptosis. Extension of the G1 phase was associated with an increased stability of the cell cycle inhibitor p27 Kip1 and reduced phosphorylation of the retinoblastoma protein Rb at serine residue 780. Our data indicate that restoration of SHIP activity in a human leukemia cell line, which has lost expression of endogenous SHIP, downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3b signaling and leads to an increased transit time through the G1 phase of the cell cycle.

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Section: Induced Expression Of Ship Affects the G1 Cell Cycle Regulatmentioning

confidence: 99%

Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle

et al. 2004

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“…In aggressive types of malignant neoplasms, downregulation of p27 has frequently been found, suggesting a tumor-suppressive role of p27 [6]. The down-regulation of p27 has been shown to be mediated predominantly through the ubiquitin-dependent proteolytic pathway [6,7]. The ubiquitin ligase activity in the ubiquitination of p27 is provided by the SCF complex, composed Skp1, Cullin-1, Rbx-1, and the p27-specific F-box protein, Skp2.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of the F‐box protein Skp2 expression in diffuse large B‐cell lymphoma

et al. 2003

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The F-box protein Skp2 positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27 kip1 (p27). Recent evidence has suggested an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. In this study, we performed immunohistochemical analysis on the cell-cycle-associated proteins, Skp2, p27, and Ki-67, in 27 patients with de novo diffuse large B-cell lymphoma (

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“…We have recently shown that targeted disruption of the Skp2 gene, which encodes the subunit of SCF Skp2 responsible for substrate recognition, results in abnormal accumulation of p27 Kip1 , suggesting that Skp2 plays an important role in regulating the abundance of this protein (19). In addition to its control by ubiquitin-mediated proteolysis, the concentration of p27 Kip1 is also regulated by protein cleavage (20) and by Jab1-mediated protein translocation from the nucleus to the cytoplasm (21).…”

Section: Down-regulation Of P27 Kip1 Expression Is Required For Develmentioning

confidence: 99%

Down-Regulation of p27Kip1 Expression Is Required for Development and Function of T Cells

Tsukiyama¹,

Ishida²,

Shirane³

et al. 2001

The Journal of Immunology

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The proliferation of T cells is regulated in a development-dependent manner, but it has been unclear whether proliferation is essential for T cell differentiation. The cyclin-dependent kinase inhibitor p27Kip1 is abundant throughout development in cells of the T cell lineage, with the exception of late stage CD4−CD8− thymocytes and activated mature T cells, both of which show a high rate of proliferation. The role of down-regulation of p27Kip1 expression in T cell development and function has now been investigated by the generation and characterization of three strains of p27 transgenic mice that express the transgene at various levels specifically in the T cell lineage. The numbers of thymocytes at CD4+CD8+, CD4+CD8−, and CD4−CD8+ stages of development as well as those of mature T cells in peripheral lymphoid tissues were reduced in transgenic mice in a manner dependent on the level of p27Kip1 expression. The development of thymocytes in the transgenic strain in which p27Kip1 is most abundant (p27-Tghigh mice) appeared to be blocked at the CD4−CD8−CD25+CD44low stage. Peripheral T cells from p27-Tghigh mice exhibited a reduced ability to proliferate in response to mitogenic stimulation compared with wild-type T cells. Moreover, Ag-induced formation of germinal centers and Ig production were defective in p27-Tghigh mice. These results suggest that down-regulation of p27Kip1 expression is required for the development, proliferation, and immunoresponsiveness of T cells.

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Down-regulation of p27 by Two Mechanisms, Ubiquitin-mediated Degradation and Proteolytic Processing

Cited by 216 publications

References 46 publications

Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle

Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle

Prognostic significance of the F‐box protein Skp2 expression in diffuse large B‐cell lymphoma

Down-Regulation of p27Kip1 Expression Is Required for Development and Function of T Cells

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