Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Vojtek, Anne B.; Taylor, Jennifer; DeRuiter, Stacy L.; Yu, Jenn Yah; Figueroa, Claudia; Kwok, Roland P.S.; Turner, David L.

doi:10.1128/mcb.23.13.4417-4427.2003

Cited by 99 publications

(93 citation statements)

References 80 publications

(95 reference statements)

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“…3). This is consistent with observations in PTEN-null mice (Groszer et al, 2001), although not consistent with the report that Akt-1 promotes a neuronal fate (Vojtek et al, 2003). This discrepancy in the impact of Akt-1 on neuron generation could reflect differences between cortical progenitors and P19 cells.…”

Section: Discussionsupporting

confidence: 78%

Akt-1 Expression Level Regulates CNS Precursors

Sinor¹,

Lillien²

2004

J. Neurosci.

109

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Although most cells in the embryonic mouse cortex express the serine-threonine kinase Akt-1, a small population of progenitors expresses Akt-1 protein at a higher level. To determine the functional significance of this difference, we used a retrovirus to increase Akt-1 expression in cortical progenitors. Increased Akt expression enhanced Akt activation after growth factor stimulation of progenitors. In vivo, it promoted retention in progenitor layers, the ventricular zone and subventricular zone. In vitro, it enhanced proliferation and survival, but did not impair migration. Moreover, it increased the proportion of stem cells, defined by a self-renewal assay. These effects did not depend on the Akt substrate p21(Cip1). In contrast, rapamycin, an inhibitor of mTOR (mammalian target of rapamycin), altered effects of elevated Akt-1 selectively: it eliminated the increase in stem cells and reduced the proliferative response, but had no effect on survival. The ability of elevated Akt-1 to increase the self-renewing population therefore depends on a rapamycin-sensitive mechanism (presumably inhibition of mTOR activity) but not on p21(Cip1), and can be distinguished from its effects on the proliferation and survival of other types of progenitors. Our findings suggest that expression of a high level of Akt-1 by a subpopulation of cortical progenitors biases their responses to extrinsic signals to increase their survival, proliferation, and/or self-renewal. Heterogeneity in Akt-1 level among progenitors could therefore allow cells that share a microenvironment to respond differently to the same extrinsic signals.

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Section: Discussionsupporting

confidence: 78%

Akt-1 Expression Level Regulates CNS Precursors

Sinor¹,

Lillien²

2004

J. Neurosci.

109

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“…Eighteen to 20 h later, the cells were transferred to Opti-MEM (Invitrogen) supplemented with 1% FBS and penicillin-streptomycin. 3-4 d after transfection, cells were fixed in 3.7% formaldehyde-phosphate-buffered saline (PBS) and stained for GFP or neuronal markers of differentiation (Farah et al, 2000;Vojtek et al, 2003). Similar results were obtained when outgrowth assays were performed on poly-l-lysine or laminin-coated dishes.…”

Section: Neuronal Differentiation Assayssupporting

confidence: 57%

The Scaffold Protein POSH Regulates Axon Outgrowth

Taylor

Chung

Figueroa

et al. 2008

MBoC

Self Cite

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How scaffold proteins integrate signaling pathways with cytoskeletal components to drive axon outgrowth is not well understood. We report here that the multidomain scaffold protein Plenty of SH3s (POSH) regulates axon outgrowth. Reduction of POSH function by RNA interference (RNAi) enhances axon outgrowth in differentiating mouse primary cortical neurons and in neurons derived from mouse P19 cells, suggesting POSH negatively regulates axon outgrowth. Complementation analysis reveals a requirement for the third Src homology (SH) 3 domain of POSH, and we find that the actomyosin regulatory protein Shroom3 interacts with this domain of POSH. Inhibition of Shroom3 expression by RNAi leads to increased process lengths, as observed for POSH RNAi, suggesting that POSH and Shroom function together to inhibit process outgrowth. Complementation analysis and interference of protein function by dominant-negative approaches suggest that Shroom3 recruits Rho kinase to inhibit process outgrowth. Furthermore, inhibition of myosin II function reverses the POSH or Shroom3 RNAi phenotype, indicating a role for myosin II regulation as a target of the POSH-Shroom complex. Collectively, these results suggest that the molecular scaffold protein POSH assembles an inhibitory complex that links to the actin-myosin network to regulate neuronal process outgrowth.

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“…One study suggests that ectopic expression of ⌬Np63␣ is sufficient to block keratinocyte differentiation (42), but the functional role of ⌬Np63␣ in this biological process remains unclear (20,41). The PI3K pathway is also implicated in the differentiation of a wide variety of cell types (43)(44)(45)(46). In epidermal keratinocytes, blockade of PI3K results in differentiation, and activation of PI3K prevents differentiation (23).…”

Section: Discussionmentioning

confidence: 99%

ΔNp63α Expression Is Regulated by the Phosphoinositide 3-Kinase Pathway

Barbieri

Barton

Pietenpol

2003

Journal of Biological Chemistry

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p63 is a homologue of p53 that functions to maintain progenitor cell populations in stratified epithelia. ⌬Np63␣ is overexpressed in epithelial cancers and has been shown to have oncogenic properties. We have previously reported that inhibition of epidermal growth factor receptor signaling results in a decrease in ⌬Np63␣ expression. Here, we demonstrate ⌬Np63␣ is a target of the phosphoinositide-3-kinase (PI3K) pathway downstream of the epidermal growth factor receptor. Treatment of keratinocytes with epidermal growth factor results in an increase in ⌬Np63␣ expression at the mRNA level, which is abrogated by inhibition of PI3K but not mitogen-activated protein kinase signaling. Small interfering RNA-mediated knockdown of the p110␤ catalytic subunit of PI3K results in a decrease in ⌬Np63␣ protein levels in keratinocytes. The results presented herein suggest that regulation of ⌬Np63␣ expression by the PI3K pathway plays a critical role in the survival and proliferative capacity of squamous epithelia.

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Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Cited by 99 publications

References 80 publications

Akt-1 Expression Level Regulates CNS Precursors

Akt-1 Expression Level Regulates CNS Precursors

The Scaffold Protein POSH Regulates Axon Outgrowth

ΔNp63α Expression Is Regulated by the Phosphoinositide 3-Kinase Pathway

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