Multiple Roles of the PI3K/PKB (Akt) Pathway in Cell Cycle Progression

Liang, Jiyong; Slingerland, Joyce M.

doi:10.4161/cc.2.4.433

Cited by 792 publications

(714 citation statements)

References 84 publications

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“…It has been concretely proved that activation of p21 and p27 prevents the binding of CDK2 with cyclin E causes cell cycle arrest in several in vitro cell lines. 32,33 In this study, SBN caused a dose-dependent decrease in cMyc protein expression. It is likely that the downregulation of cMyc protein expression accompanied by up regulation of p21and p27 would have caused the cell cycle arrest through the inhibition of cyclin E binding with CDK2.…”

Section: Journal Of Clinical and Experimental Hepatologysupporting

confidence: 49%

Silibinin Inhibits Proliferation and Migration of Human Hepatic Stellate LX-2 Cells

Ezhilarasan

Evraerts

Sid

et al. 2016

Journal of Clinical and Experimental Hepatology

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Background: Proliferation of hepatic stellate cells (HSCs) play pivotal role in the progression of hepatic fibrosis consequent to chronic liver injury. Silibinin (SBN), a flavonoid compound, has shown to possess cell cycle arresting potential against many actively proliferating cancers cell lines. The objective of this study was to evaluate the anti-proliferative and cell cycle arresting properties of SBN in rapidly proliferating human hepatic stellate LX-2 cell line. Methods: LX-2 cells were fed with culture medium supplemented with different concentrations of SBN (10, 50 and 100 mM). After 24 and 96 h of treatment, total cell number was determined by counting. Cytotoxicity was evaluated by trypan blue dye exclusion test. The expression profile of cMyc and peroxisome proliferator-activated receptor-g (PPAR-g) protein expressions was evaluated by Western blotting. Oxidative stress marker genes profile was quantified using qPCR. The migratory response of HSCs was observed by scrape wound healing assay. Results: SBN treatments significantly inhibit the LX-2 cell proliferation (without affecting its viability) in dose dependent manner. This treatment also retards the migration of LX-2 cells toward injured area. In Western blotting studies SBN treatment up regulated the protein expressions of PPAR-g and inhibited cMyc. Conclusion: The present study shows that SBN retards the proliferation, activation and migration of LX-2 cells without inducing cytotoxicity and oxidative stress. The profound effects could be due to cell cycle arresting potential of SBN. ( J CLIN EXP HEPATOL 2016;6:167-174)

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Section: Journal Of Clinical and Experimental Hepatologysupporting

confidence: 49%

Silibinin Inhibits Proliferation and Migration of Human Hepatic Stellate LX-2 Cells

Ezhilarasan

Evraerts

Sid

et al. 2016

Journal of Clinical and Experimental Hepatology

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“…b-catenin and cyclin D1 can be positively regulated by AKT signaling and in turn regulate the G1-S phase transition during cell cycle progression. 31,32 The expression of the ACK1 Y635F mutant (higher than endogenous ACK1 levels) but not the ACK1 Y859F mutant (higher than endogenous ACK1 levels) dramatically blocked the PDGF-induced upregulation of cyclin D1 protein levels and nuclear levels of b-catenin in U87 and U251 cells (Figs. 4a left panel and 4b left panel).…”

Section: Ack1 Is Critical For Downstream Signaling Of Pdgf-pdgfrmentioning

confidence: 97%

PDGFR‐β‐activated ACK1‐AKT Signaling Promotes Glioma Tumorigenesis

Zhang

Chen

Qin

et al. 2014

Intl Journal of Cancer

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Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-b activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-b and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-b phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-b. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-b-induced AKT activation, the subsequent nuclear translocation of bcatenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-b activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment.

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“…Multiple signaling pathways could lead to the upregulation of cyclin D1, including Wnt and PI3K/AKT pathways. 26,27 The activation of Wnt signaling pathway facilitates the accumulation and nuclear translocation of b-catenin and subsequently induces the target gene expression. CCND1 encoding cyclin D1 is one of the target genes.…”

Section: Sox11 In B-cell Neoplasmsmentioning

confidence: 99%

“…29 Interestingly, activation of this pathway not only promotes the antiapoptotic signaling but also increases the expression of cyclin D1. 27 Further investigation of the possibility of activation of these pathways by sox11 may help to uncover the molecular mechanisms underlying the upregulation of cyclin D1 in hairy cell leukemia.…”

Section: Sox11 In B-cell Neoplasmsmentioning

confidence: 99%

Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms

et al. 2010

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Sox11 is a transcription factor involved in embryonic neurogenesis and tissue remodeling. Its role in lymphopoiesis is presently unknown. Recent studies have shown the nuclear expression of sox11 in mantle cell lymphoma, which raises the question about its possible association with t(11;14)(q13;q32), the genetic hallmark of mantle cell lymphoma leading to the overexpression of cyclin D1. In this study, we examined sox11 expression in 211 cases of B-cell neoplasms by immunohistochemistry, and evaluated its association with t(11;14) and overexpression of cyclin D1. Nuclear staining of sox11 was observed in 54 of 57 (95%) mantle cell lymphomas, including 52 of 53 (98%) classical and 2 of 4 variant types. Two of the three mantle cell lymphomas negative for nuclear sox11 staining were analyzed and were positive for t(11;14). All other B-cell lymphomas (114 cases) showed variable positive staining in the cytoplasm, but no nuclear positivity. Sox11 was then examined in plasma cell myeloma and hairy cell leukemia as a subset of plasma cell myeloma carry t(11;14) and overexpress cyclin D1, and cyclin D1 is overexpressed in a subset of hairy cell leukemia independent of t(11;14). We found no nuclear staining of sox11 in 30 plasma cell myelomas examined, including 12 cases with t(11;14)(q13;q32). It is interesting that intense nuclear staining of sox11 was present in a subset of hairy cell leukemias (5 of 10), and was associated with the overexpression of cyclin D1. Our results indicate that the nuclear expression of sox11 is highly associated with mantle cell lymphoma, but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms. Its association with the overexpression of cyclin D1 in hairy cell leukemia suggests that sox11 may be involved in the upregulation of cyclin D1 in this leukemia.

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Multiple Roles of the PI3K/PKB (Akt) Pathway in Cell Cycle Progression

Cited by 792 publications

References 84 publications

Silibinin Inhibits Proliferation and Migration of Human Hepatic Stellate LX-2 Cells

Silibinin Inhibits Proliferation and Migration of Human Hepatic Stellate LX-2 Cells

PDGFR‐β‐activated ACK1‐AKT Signaling Promotes Glioma Tumorigenesis

Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms

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