SDF-1 synergistically enhances IL-3-induced activation of the Raf-1/MEK/Erk signaling pathway through activation of Rac and its effector Pak kinases to promote hematopoiesis and chemotaxis

Arai, Ayako; Jin, Aishun; Yan, Wei; Mizuchi, Daisuke; Yamamoto, Koh; Nanki, Toshihiro; Miura, Osamu

doi:10.1016/j.cellsig.2004.09.007

Cited by 32 publications

(21 citation statements)

References 45 publications

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“…In accordance with these results, previous studies indicate that Rac activates the RAF/MEK/ERK pathway (16,17) and that Rac/ PAK regulation of ERK is essential for HER2-induced transformation of human breast epithelial cancer cells (20). However, the regulation of ERK signaling in a PI3K-dependent manner via P-Rex1 has not been previously described.…”

Section: Discussionsupporting

confidence: 77%

“…Previous research has identified alternative mechanisms for activating ERK signaling, and thus we turned our attention to Rac, the small GTPase that is a key downstream effector of PI3K signaling (15). It has been shown that Rac can activate PAK (p21-activated kinase), which can directly activate the RAF/MEK/ERK pathway (16,17). To measure Rac1 activity, cells were serum starved and then changed into media containing 10% (vol/vol) FBS with or without PI3K inhibitor.…”

Section: Resultsmentioning

confidence: 99%

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PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Ebi

Costa

Faber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

182

163

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The PI3K pathway is genetically altered in excess of 70% of breast cancers, largely through PIK3CA mutation and HER2 amplification. Preclinical studies have suggested that these subsets of breast cancers are particularly sensitive to PI3K inhibitors; however, the reasons for this heightened sensitivity are mainly unknown. We investigated the signaling effects of PI3K inhibition in PIK3CA mutant and HER2 amplified breast cancers using PI3K inhibitors currently in clinical trials. Unexpectedly, we found that in PIK3CA mutant and HER2 amplified breast cancers sensitive to PI3K inhibitors, PI3K inhibition led to a rapid suppression of Rac1/p21-activated kinase (PAK)/protein kinase C-RAF (C-RAF)/ protein kinase MEK (MEK)/ERK signaling that did not involve RAS. Furthermore, PI3K inhibition led to an ERK-dependent up-regulation of the proapoptotic protein, BIM, followed by induction of apoptosis. Expression of a constitutively active form of Rac1 in these breast cancer models blocked PI3Ki-induced down-regulation of ERK phosphorylation, apoptosis, and mitigated PI3K inhibitor sensitivity in vivo. In contrast, protein kinase AKT inhibitors failed to block MEK/ERK signaling, did not upregulate BIM, and failed to induce apoptosis. Finally, we identified phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) as the PI(3,4,5)P3-dependent guanine exchange factor for Rac1 responsible for regulation of the Rac1/C-RAF/MEK/ERK pathway in these cells. The expression level of P-Rex1 correlates with sensitivity to PI3K inhibitors in these breast cancer cell lines. Thus, PI3K inhibitors have enhanced activity in PIK3CA mutant and HER2 amplified breast cancers in which PI3K inhibition down-regulates both the AKT and Rac1/ERK pathways. In addition, P-Rex1 may serve as a biomarker to predict response to single-agent PI3K inhibitors within this subset of breast cancers.

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Ebi

Costa

Faber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

182

163

View full text Add to dashboard Cite

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“…The SDF-1/ CXCR4 axis plays an important role in the adhesion and migration of leukemia cells to the bone marrow matrix. SDF-1 induces chemotaxis of various hematopoietic cells along its concentration gradient, and also regulates the activity of extracellular signal-regulated kinase through the SDF-1/CXCR4 signaling system, which directly affects the integrin-mediated cell adhesion (21,22). In the present study, we found that the adhesion rate of Jurkat cells was significantly reduced when they were co-cultured with HIF-1α-silenced acute leukemia hBMSCs compared to coculture with normal hBMSCs, suggesting that HIF-1α may influence the adhesion capacity of hBMSCs to leukemia cells by regulating SDF-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Zeng¹,

Liu²,

Chen³

et al. 2012

Braz J Med Biol Res

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Hypoxia inducible factor-1α (HIF-1α) is an important transcription factor, which plays a critical role in the formation of solid tumor and its microenvironment. The objective of the present study was to evaluate the expression and function of HIF-1α in human leukemia bone marrow stromal cells (BMSCs) and to identify the downstream targets of HIF-1α. HIF-1α expression was detected at both the RNA and protein levels using real-time PCR and immunohistochemistry, respectively. Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) were detected in stromal cells by enzyme-linked immunosorbent assay. HIF-1α was blocked by constructing the lentiviral RNAi vector system and infecting the BMSCs. The Jurkat cell/BMSC co-cultured system was constructed by putting the two cells into the same suitable cultured media and conditions. Cell adhesion and secretion functions of stromal cells were evaluated after transfection with the lentiviral RNAi vector of HIF-1α. Increased HIF-1α mRNA and protein was detected in the nucleus of the acute myeloblastic and acute lymphoblastic leukemia compared with normal BMSCs. The lentiviral RANi vector for HIF-1α was successfully constructed and was applied to block the expression of HIF-1α. When HIF-1α of BMSCs was blocked, the expression of VEGF and SDF-1α secreted by stromal cells was decreased. When HIF-1α was blocked, the co-cultured Jurkat cell's adhesion and migration functions were also decreased. Taken together, these results suggest that HIF-1α acts as an important transcription factor and can significantly affect the secretion and adhesion functions of leukemia BMSCs.

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“…Similar to the tachykinins, the chemokine stromal-derived growth factor (SDF)-1␣ is also involved in hemopoiesis (8). The production of SDF-1␣ in BM stromal cells is membrane-bound and available for interaction with the CXCR4-expressing hemopoietic stem cells (HSCs) (9,10).…”

mentioning

confidence: 99%

“…However, changes in this gradient facilitate HSC mobilization of the BM; into the peripheral circulation (9). Stromal-derived SDF-1␣ is important for the quiescent state of HSC close to the BM niche, whereas changes in the levels of SDF-1␣ have been shown to stimulate hemopoiesis (8,13).…”

mentioning

confidence: 99%

Stromal Derived Growth Factor-1α: Another Mediator in Neural-Emerging Immune System through Tac1 Expression in Bone Marrow Stromal Cells

Corcoran¹,

Patel²,

Rameshwar

2007

The Journal of Immunology

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Stromal cell-derived growth factor-1α (SDF-1α) is a member of the CXC chemokines and interacts with the G protein, seven-transmembrane CXCR4 receptor. SDF-1α acts as a chemoattractant for immune and hemopoietic cells. The Tac1 gene encodes peptides belonging to the tachykinin family with substance P being the predominant member. Both SDF-1α and Tac1 peptides are relevant hemopoietic regulators. This study investigated the effects of SDF-1α on Tac1 expression in the major hemopoietic supporting cells, the bone marrow stroma, and addresses the consequence to hemopoiesis. Reporter gene assays with the 5′ flanking region of Tac1 showed a bell-shaped effect of SDF-1α on luciferase activity with 20 ng/ml SDF-1α acting as stimulator, whereas 50 and 100 ng/ml SDF-1α acted as inhibitors. Gel shift assays and transfection with wild-type and mutant IκB indicate NF-κB as a mediator in the repressive effects at 50 and 100 ng/ml SDF-1α. Northern analyses and ELISA showed correlations among reporter gene activities, mRNA (β-preprotachykinin I), and protein levels for substance P. Of relevance is the novel finding by long-term culture-initiating cell assays that showed an indirect effect of SDF-1α on hemopoiesis through substance P production. The results also showed neurokinin 1 and not neurokinin 2 as the relevant receptor. Another crucial finding is that substance P does not regulate the production of SDF-1α in stroma. The studies indicate that SDF-1α levels above baseline production in bone marrow stroma induce the production of substance P to stimulate hemopoiesis. Substance P, however, does not act as autocrine stimulator to induce the production of SDF-1α. This study adds SDF-1α as a mediator within the neural-immune-hemopoietic axis.

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SDF-1 synergistically enhances IL-3-induced activation of the Raf-1/MEK/Erk signaling pathway through activation of Rac and its effector Pak kinases to promote hematopoiesis and chemotaxis

Cited by 32 publications

References 45 publications

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Stromal Derived Growth Factor-1α: Another Mediator in Neural-Emerging Immune System through Tac1 Expression in Bone Marrow Stromal Cells

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