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MTOR PDCD4 (1 - 2 of 2)
PMID: 21771721
Inflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation.
... characterized PI3K-mTOR-dependent proteasome-mediated Pdcd4 degradation ...   (details)

MTOR PDCD4

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 21771721

Inflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation.
Source

Carcinogenesis (October 2011)

Abstract

Inflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation. The tumor suppressor programmed cell death 4 (Pdcd4) is lost in various tumor tissues. Loss of Pdcd4 has been associated with increased tumorigenic potential and tumor progression. While various mechanisms of Pdcd4 regulation have been described, the effect of an inflammatory tumor microenvironment on Pdcd4 protein expression has not been characterized so far. In the present study, we aimed to elucidate the molecular mechanisms of Pdcd4 protein regulation in tumor cells under inflammatory conditions. 12-O-tetradecanoylphorbol 13-acetate-induced differentiation of human U937 monocytes increased the expression and secretion of inflammatory cytokines such as tumor necrosis factor a, interleukin (IL) -6 and IL-8. Exposure to conditioned medium (CM) of these activated macrophages markedly decreased Pdcd4 protein expression in various tumor cells. Similarly, indirect coculture with such activated U937 monocyte-derived macrophages resulted in the loss of Pdcd4 protein in tumor cells. Decreased Pdcd4 protein levels were attributable to enhanced proteasomal degradation, diminishing Pdcd4 protein half-life. Proteasomal degradation required activation of phosphatidylinositol-3-kinase (PI3K) -mammalian target of rapamycin (mTOR) signaling. Since macrophage-CM sufficed to induce Pdcd4 degradation, Pdcd4 downregulation was determined to be an indirect unidirectional effect of the macrophages on the tumor cells. Pdcd4 protein expression was also attenuated in vivo in mouse colon tissue in response to dextran sodium sulfate-induced colitis. In summary, we characterized PI3K-mTOR-dependent proteasome-mediated Pdcd4 degradation in tumor cells in the inflammatory tumor microenvironment. Consequently, stabilization of Pdcd4 protein could provide a promising novel avenue for therapeutics targeting inflammation-associated tumors.

PMID: 23281820
Rapamycin Enhances TNF-a-Induced Secretion of IL-6 and IL-8 through Suppressing PDCD4 Degradation in Orbital Fibroblasts.
... the mTOR-dependent proteasome ... of PDCD4.   (details)

MTOR PDCD4

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 23281820

Rapamycin Enhances TNF-a-Induced Secretion of IL-6 and IL-8 through Suppressing PDCD4 Degradation in Orbital Fibroblasts.
Source

Current eye research (June 2013)

Abstract

Rapamycin Enhances TNF-a-Induced Secretion of IL-6 and IL-8 through Suppressing PDCD4 Degradation in Orbital Fibroblasts. Purpose: To investigate the effects of rapamycin on the TNF-a-induced secretion of interleukin-6 (IL-6) and IL-8 in orbital fibroblasts and its possible mechanism. Materials and methods: Orbital fibroblasts were obtained from patients with thyroid-associated ophthalmopathy. IL-6 and IL-8 levels were measured by enzyme-linked immunosorbent assays. The down-regulation of PDCD4 was performed by PDCD4 siRNA transfection. Results: Rapamycin significantly enhanced TNF-a-induced IL-6 and IL-8 secretion from orbital fibroblasts. Down-regulation of PDCD4 by PDCD4 siRNA transfection reduced TNF-a-induced IL-6 and IL-8 secretion from orbital fibroblasts. In addition, TNF-a was found to promote the mTOR-dependent proteasome-mediated degradation of PDCD4. Rapamycin increased PDCD4 expression via the inhibition of TNF-a-induced PDCD4 degradation in orbital fibroblasts. Conclusion: Rapamycin enhances the TNF-a-induced secretion of IL-6 and IL-8 by suppressing PDCD4 degradation in orbital fibroblasts.