p27Kip1 Localizes to Detergent-insoluble Microdomains Within Lymphocyte Membranes

Yaroslavskiy, Beatrice B.; Stolz, Donna B.; Watkins, Simon C.; Alber, Sean; Bradbury, Neil A.; Steinman, Richard A.

doi:10.1007/bf03401838

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…In rat hepatocytes, Cdk2 has been reported to modulate receptor activation at the plasma membrane by regulating endocytosis (Gaulin et al, 2000). We have shown that the cdk2-inhibitor p27 also may interact with signaling complexes by localizing to lipid rafts (Yaroslavskiy et al, 2001) Such localization could facilitate 'inside-out' signaling of cell cycle regulators to alter signal transduction at the membrane. Indeed, recent reports that Stat3 localizes to rafts (Sehgal et al, 2002) and that stat3 undergoes endocytosis during signaling (Bild et al, 2002) indicate that Stat3 may share topographic proximity with cdk2 and cdk2 inhibitors at the cell membrane.…”

Section: Discussionmentioning

confidence: 95%

Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2

Steinman

Wentzel

et al. 2003

Oncogene

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The signal transducing protein Stat3 activates gene transcription in cells in response to multiple cytokines. Constitutive activation of Stat3 has been observed in solid tumors including head and neck squamous cell carcinoma. Stat3 activation in cancer has been associated with autocrine stimulatory loops and is believed to convey a growth advantage to cells. We now demonstrate ligandindependent activation of Stat3 by high cell density in multiple cancer cell lines. Activation of Stat3 is associated with antiproliferative rather than proliferative conditions. Interference with cdk2 activity upregulates Stat3 phosphorylation and Stat3-directed DNA-binding activity. Our data supports a model in which Stat3 activity is partially suppressed by cdk2 in growing cells and derepressed upon cell confluence.

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Section: Discussionmentioning

confidence: 95%

Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2

Steinman

Wentzel

et al. 2003

Oncogene

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“…Cytoplasmic displacement/sequestration of p27 Kip1 has been reported to be a potential mechanism of its inactivation (Barnouin et al , 1999). More recently, p27 Kip1 has been associated with detergent‐insoluble microdomains of lymphocyte membranes, known as rafts, which are thought to provide a scaffold for signalling proteins (Yaroslavskiy et al , 2001). As the localization of proteins within raft structures is thought to be important for cell signalling, it is likely that the localization of p27 Kip1 in these structures have a significant impact in the cell's response to signalling molecules.…”

Section: Discussionmentioning

confidence: 99%

Growth regulation by p27^Kip1 is abrogated by multiple mechanisms in aggressive malignant lymphomas

Lin¹,

Lim²,

Lim³

2003

Br J Haematol

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Summary. The cyclin‐dependent kinase inhibitor p27Kip1 is a key regulator of the G1/S transition, and an inverse relationship between p27Kip1 protein expression and proliferation index has been reported in malignant lymphomas. However, a subset of aggressive B‐cell lymphomas demonstrates high p27Kip1 expression despite a high proliferation index. The aim of this study was to determine potential mechanisms by which lymphoma cells abrogate the growth inhibitory effect of high p27Kip1. The effect of transforming growth factor‐β (TGF‐β) and serum stimulation on p27Kip1 expression and cyclin E/cdk2 activity was investigated in four lymphoma cell lines, Jurkat, CEM‐6, OCI‐Ly1 and Nalm‐6. Reactive lymphocytes responded to growth inhibitory TGF‐β by inducing p27Kip1 expression, with subsequent accumulation of cells in G0/G1. In contrast, TGF‐β did not alter the level of p27Kip1 in Jurkat, CEM‐6 and OCI‐Ly1 cells with no change in cyclin E/cdk2‐kinase activity. Serum stimulation also did not result in a significant change in p27Kip1 expression. Western blot analysis of subcellular fractions demonstrated cytoplasmic p27Kip1, corroborated by immunocytochemistry in a subset of the lymphoma cells. Sequestration of p27Kip1 by cyclin D3 was observed in the nuclear and cytoplasmic fractions of Nalm‐6, OCI‐Ly‐1 and NCEB cells. These results indicate that multiple mechanisms contribute to the abrogation of growth regulation by unscheduled high p27Kip1 protein expression including deficient response to TGF‐β and serum, sequestration by cyclin D3 and cytoplasmic displacement.

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“…It was shown that TNFR1 needs to be recruited to lipid rafts in order to mediate NFκB activation and that any interference with the lipid raft organization may switch TNF-signaling from NFκB activation to apoptosis in the human fibrosarcoma cells (42). Interestingly, membrane rafts in normal lymphocytes were also reported to contain p27 Kip1 , and it was suggested that p27 Kip1 may play a role in modulating membrane signaling, since it was excluded from the rafts upon lymphocytes activation (43). By taking these two together, it would be tempting to speculate that in Adp27-infected PC-3 cells, p27 Kip1 remains in lipid rafts thus preventing the activation of NFκB, and promoting the signaling to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

TNF receptor 1 is involved in the induction of apoptosis by the cyclin‐dependent kinase inhibitor p27^Kip1in the prostate cancer cell line PC‐3

Jaruga-Killeen

Rayford

2004

FASEB j.

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Loss of p27Kip1, a cyclin-dependent kinase inhibitor, is observed in aggressive prostate cancers. We demonstrated that intratumoral injections of recombinant adenovirus overexpressing p27Kip1 (Adp27) reduced the growth of prostate cancer xenografts in nude mice. Presently, we studied the mechanism(s) of cell death induced by Adp27 in prostate cancer cell line PC-3. Cells were infected with Adp27 and compared with those infected by empty virus or were non-infected. Cell cycle and typical markers of apoptosis were analyzed by flow cytometry in the presence of the following reagents: cycloheximide, pan-caspase inhibitor ZVAD-fmk, neutralizing anti-TNFR1, and anti-TNFR2. Overexpression of p27Kip1 protein and cell cycle arrest were noted within 24 h after Adp27-infection. Sub-G1 fraction, chromatin margination, and phosphatidylserine exposure were evident by the third day of treatment. Cycloheximide elevated sub-G1 fraction in Adp27-infected cells by threefold, while ZVAD-fmk reduced sub-G1 to control levels. Caspase-dependent apoptosis occurred in a third of the population, while two-thirds were ZVAD-fmk insensitive but TUNEL-positive. Flow cytometry showed increased expression of TNFR1 and TNFR2 in Adp27-infected cells. Neutralizing anti-TNFR1 decreased TUNEL-positive score, while anti-TNFR2 did not affect p27Kip1-induced apoptosis. This is the first report showing that p27Kip1 induces caspase-dependent and -independent stages of cell death that may involve TNF-signaling through TNFR1.

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p27Kip1 Localizes to Detergent-insoluble Microdomains Within Lymphocyte Membranes

Abstract: This study identifies, for the first time, the localization of p27 within a membrane microdomain associated with signaling. Because some cell surface signaling complexes lose p27Kip1 upon cellular activation, p27Kip1 may play a functional role in modulating membrane signaling.

Cited by 4 publications

References 47 publications

Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2

Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2

Growth regulation by p27^Kip1 is abrogated by multiple mechanisms in aggressive malignant lymphomas

TNF receptor 1 is involved in the induction of apoptosis by the cyclin‐dependent kinase inhibitor p27^Kip1in the prostate cancer cell line PC‐3

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p27Kip1 Localizes to Detergent-insoluble Microdomains Within Lymphocyte Membranes

Abstract: This study identifies, for the first time, the localization of p27 within a membrane microdomain associated with signaling. Because some cell surface signaling complexes lose p27Kip1 upon cellular activation, p27Kip1 may play a functional role in modulating membrane signaling.

Cited by 4 publications

References 47 publications

Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2

Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2

Growth regulation by p27Kip1 is abrogated by multiple mechanisms in aggressive malignant lymphomas

TNF receptor 1 is involved in the induction of apoptosis by the cyclin‐dependent kinase inhibitor p27Kip1in the prostate cancer cell line PC‐3

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Product

Resources

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Growth regulation by p27^Kip1 is abrogated by multiple mechanisms in aggressive malignant lymphomas

TNF receptor 1 is involved in the induction of apoptosis by the cyclin‐dependent kinase inhibitor p27^Kip1in the prostate cancer cell line PC‐3