Ras/Erk MAPK Signaling in Epidermal Homeostasis and Neoplasia

Khavari, Thomas A.; Rinn, John L.

doi:10.4161/cc.6.23.4998

Cited by 125 publications

(101 citation statements)

References 43 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Additionally, the increased expression of CKIs in the epidermis of mutant mice can also contribute to the proliferative defect found. Because ERK and AKT are essential for skin proliferation and cyclin D1 expression (38,39,56), it would be expected a reduced activity of these kinases in TR KO mice, but paradoxically stimulation rather than inhibition was found in these animals, indicating that other still unidentified pathways dependent on the receptors are responsible for the reduction of cyclin D1. Because expression of the cyclin D1 gene is under the control of a panoply of transcription factors that are modulated by these kinases, the reduced cyclin D1 expression observed could indicate that the TRs and its ligand are required for the activity of those tran- scription factors or that they are essential direct modulators of cyclin D1 expression in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

show abstract

Section: Discussionmentioning

confidence: 99%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…On the contrary, deletion of the cytoplasmic proteins associated with cadherin cell-cell adhesions, a-or p120-catenin, leads to hyperproliferative epidermis because of sustained activation of the Ras-MAPK pathway (Vasioukhin et al 2001;Perez-Moreno et al 2006). Consistent with its role as a regulator of proliferation versus differentiation in the epidermis, MAPK signaling is crucial for epidermal tumor formation, and indeed most squamous cell carcinomas (SCCs) are characterized by activation of the Ras pathway and up-regulation of MAPK activity (Khavari and Rinn 2007).…”

Section: Epidermal Stratification Renewal and Differentiationmentioning

confidence: 94%

Development and Homeostasis of the Skin Epidermis

Sotiropoulou

Blanpain

2012

Cold Spring Harbor Perspectives in Biology

View full text Add to dashboard Cite

SUMMARYThe skin epidermis is a stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections. The epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behavior. The epidermis undergoes a constant turnover and distinct stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments. Deregulation of the signaling pathways controlling the balance between renewal and differentiation often leads to cancer formation.

show abstract

“…To our knowledge, extracellular signalregulated kinase (ERK)/mitogen-activated protein kinases (MAPKs) pathway plays a crucial role in almost all cell functions. Phosphorylation of ERK is activated in response to many kinds of stress and the activity of ERK can mediate two apparently opposing processes from cell proliferation to cell death (Cagnol and Chambard 2010;Khavari and Rinn 2007;Mebratu and Tesfaigzi 2009). There is now increasing evidence that ERK has the dual effects in hypoxia and compounds that influence ERK can function as protective agents (Montagut and Settleman 2009;Muslin 2008;Ohori 2008).…”

Section: Introductionmentioning

confidence: 99%

The protective role of 5-HMF against hypoxic injury

Wu²,

Zhao³

et al. 2011

Cell Stress and Chaperones

View full text Add to dashboard Cite

In an attempt to find new types of anti-hypoxic agents from herbs, we identified 5-hydroxymethyl-2-furfural (5-HMF) as a natural agent that fulfills the criterion. 5-HMF, the final product of carbohydrate metabolism, has favorable biological effects such as anti-oxidant activity and inhibiting sickling of red blood cells. The role of 5-HMF in hypoxia, however, is not yet. Our pilot results showed that pretreatment with 5-HMF markedly increased both the survival time and the survival rate of mice under hypoxic stress. The present study was aimed to further investigate the protective role of 5-HMF and the underlying mechanisms in hypoxic injury using ECV304 cells as an in vitro model. ECV304 cells pretreated with or without 5-HMF for 1 h were exposed to hypoxic condition (0.3% O 2 ) for 24 h and then cell apoptosis, necrosis, the changes of mitochondrial membrane potential (MMP) and the expressions of phosphorylation-extracellular signal-regulated kinase (p-ERK) were investigated. Pretreatment with 5-HMF markedly attenuated hypoxia-induced cell necrosis and apoptosis at late stage (p<0.01). Furthermore, pretreatment with 5-HMF rescued both the decline of the MMP and the increase of p-ERK protein under hypoxia. In a word, these results indicated that 5-HMF had protective effects against hypoxic injury in ECV304 cells, and its effects on MMP and p-ERK may be involved in the mechanism.

show abstract

Ras/Erk MAPK Signaling in Epidermal Homeostasis and Neoplasia

Cited by 125 publications

References 43 publications

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Development and Homeostasis of the Skin Epidermis

The protective role of 5-HMF against hypoxic injury

Contact Info

Product

Resources

About