AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes

Thrash, Barry R.; Menges, Craig W.; Pierce, Robert H.; McCance, Dennis J.

doi:10.1074/jbc.m512116200

Cited by 66 publications

(77 citation statements)

References 46 publications

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“…The activation of Akt in differentiating cells prevents premature apoptosis even in the depletion of integrin binding to extracellular matrices, allowing the cells to complete their differentiation. Consistent with this, Akt knockdown enhances apoptosis of keratinocytes during differentiation (Thrash et al, 2006). Akt is kept inactivated in immature cells in the absence of stress; however, UV-B was shown to activate Akt through many signaling molecules, including the epidermal growth factor receptor (Wang et al, 2003).…”

Section: P51-dependent Protection Of Uv-b-irradiated Keratinocytes Issupporting

confidence: 52%

p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

et al. 2007

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The epidermis must be protected against excess apoptotic cell death in response to ultraviolet-B (UV-B) irradiation. p53 is known to be critical for this protection. Although the p53 family member DNp51B/DNp63a (an N terminaldeleted form of p51/p63) is abundantly expressed in keratinocytes, its contribution to UV-B-dependent apoptosis is largely unknown. We found that, after a transient increase, DNp51B is downregulated in UV-B-irradiated keratinocytes undergoing apoptosis, whereas p53 is upregulated with delayed kinetics. Furthermore, the reduction of DNp51B by small interfering RNAs augmented UV-B-dependent apoptosis in keratinocytes, indicating that DNp51B blocks keratinocyte apoptosis. Although the exogenous expression of DNp51B in keratinocytes did not further block the UV-B-dependent apoptosis, to our surprise the expression of TAp51B (an isoform with a full NH 2 -terminal transactivation domain that is structurally and functionally similar to p53) decreased apoptosis significantly. The blockade of keratinocyte apoptosis by the p51 was dependent on the phosphorylation of Akt, resulting in the activation of a survival pathway. Thus, in addition to its indispensable roles in epithelial development, p51 acts in adult cells to protect the epidermis against UV-B irradiation by preventing excess depletion of keratinocytes.

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Section: P51-dependent Protection Of Uv-b-irradiated Keratinocytes Issupporting

confidence: 52%

p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

et al. 2007

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“…shScram was cloned and described previously (Thrash et al, 2006). shRNA against EphA 2 was cloned into pSuper-retro-puro (OligoEngine) as previously described (Thrash et al, 2006) with the following primers: sense 5 0 -GATCCCCGGACCCAGCTAAGCACTTATTCAA GAGATAAGTGCTTAGCTGGGTCCTTTTTGGAAA-3 0 ; antisense 5 0 -AGCTTTTCCAAAAAGGACCCAGCTAAGCA CTTATCTCTTGAATAAGTGCTTAGCTGGGTCCGGG-3 0 .…”

Section: Methodsmentioning

confidence: 99%

Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

Menges

McCance

2007

Oncogene

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The Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf-MAPK and PI3K-AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K-AKT pathway can inhibit the Raf-MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf-MAPK pathway to negatively regulate the PI3K-AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf-MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA 2 . EphA 2 -mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras-PI3K-AKT pathway as a necessary event for the Raf-MEK1-regulated cellular arrest.

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“…Following recent reports of Akt involvement with keratinocyte differentiation (16 -18) Ser 473 phosphorylated Akt (pSerAkt) expression was monitored over this critical period because it has been shown to accurately indicate keratinocyte Akt activity (18). pSerAkt was expressed in the lower epidermal strata at E16.5 (parabasal, post-mitotic cells; Fig.…”

Section: Phosphorylated Akt and Hspb1 Show Distinct Expressionmentioning

confidence: 99%

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

O'Shaughnessy

Welti

Cooke

et al. 2007

Journal of Biological Chemistry

117

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AKT activity has been reported in the epidermis associated with keratinocyte survival and differentiation. We show in developing skin that Akt activity associates first with post-proliferative, para-basal keratinocytes and later with terminally differentiated keratinocytes that are forming the fetal stratum corneum. In adult epidermis the dominant Akt activity is in these highly differentiated granular keratinocytes, involved in stratum corneum assembly. Stratum corneum is crucial for protective barrier activity, and its formation involves complex and poorly understood processes such as nuclear dissolution, keratin filament aggregation, and assembly of a multiprotein cell cornified envelope. A key protein in these processes is filaggrin. We show that one target of Akt in granular keratinocytes is HspB1 (heat shock protein 27). Loss of epidermal HspB1 caused hyperkeratinization and misprocessing of filaggrin. Akt-mediated HspB1 phosphorylation promotes a transient interaction with filaggrin and intracellular redistribution of HspB1. This is the first demonstration of a specific interaction between HspB1 and a stratum corneum protein and indicates that HspB1 has chaperone activity during stratum corneum formation. This work demonstrates a new role for Akt in epidermis.The epidermis is the primary environmental barrier, protecting from infection, allergens, and damage from UV radiation. The major constituent of this epidermal barrier is the terminally differentiated, anuclear keratinocyte. This structure is bounded by a cornified envelope, an elaborate, cross-linked protein structure covalently bound to hydrophobic lipid externally and aggregated keratin internally (1). Formation of this structure is poorly understood.The complexity of keratinocyte terminal differentiation and the importance of precisely timed and compartmentalized processing is illustrated by the maturation of the stratum corneum protein filaggrin. Filaggrin is synthesized as a high molecular mass precursor comprising multiple subunits that are sequentially processed and modified in temporally and spatially regulated steps by diverse proteases and enzymes to produce mature filaggrin subunits. Mature filaggrin is thought to be important in the aggregation and collapse of the keratin network leading to flattening of the keratinocyte and the destruction of the nucleus in granular layer (terminally differentiating) keratinocytes (2). Filaggrin is also incorporated into the cornified envelope (2). Premature or aberrant filaggrin processing can be catastrophic, leading to disruption of cornified envelope integrity and skin barrier function (3-5) and is far more damaging than reduced filaggrin levels that, in contrast, lead only to mild skin defects (6).Possible regulators of protein processing and trafficking during terminal differentiation are heat shock proteins (Hsps). 2Hsps have diverse roles as cellular chaperones, anti-apoptotic factors, stress-protective proteins, and cytoskeletal stabilizers (7,8). Human HspB1 (Hsp27) (9 -11) and the mouse HspB1...

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AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes

Cited by 66 publications

References 46 publications

p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

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