Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not tumor promotion

1999 ◽  
Vol 112 (20) ◽  
pp. 3497-3506
Author(s):  
H.Q. Wang ◽  
R.C. Smart
Keyword(s):  
Protein Kinase ◽  
Transgenic Mice ◽  
Normal Mouse ◽  
Mouse Skin ◽  
Tumor Promotion ◽  
Epidermal Differentiation ◽  
Wild Type ◽  
Outer Root Sheath ◽  
Proinflammatory Mediators ◽  
Cox 2

Protein kinase Calpha (PKCalpha) is one of six PKC isoforms expressed in keratinocytes of mouse epidermis. To gain an understanding of the role of epidermal PKCalpha, we have localized its expression to specific cells of normal mouse skin and examined the effect of keratin 5 (K5) promoter directed expression of PKCalpha in transgenic mice. In normal mouse skin, PKCalpha was extensively expressed in the outer root sheath (ORS) keratinocytes of the anagen hair follicle and weakly expressed in keratinocytes of interfollicular epidermis. K5-targeted expression of PKCalpha to epidermal basal keratinocytes and follicular ORS keratinocytes resulted in a tenfold increase in epidermal PKCalpha. K5-PKCalpha mice exhibited no abnormalities in keratinocyte growth and differentiation in the epidermis. However, a single topical treatment with the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a striking inflammatory response characterized by edema and extensive epidermal infiltration of neutrophils that formed intraepidermal microabscesses in the epidermis. Compared to TPA-treated wild-type mice, the epidermis of TPA-treated K5-PKCalpha mice displayed increased expression of cyclooxygenase-2 (COX-2), the neutrophil chemotactic factor macrophage inflammatory protein-2 (MIP-2) mRNA and the proinflammatory cytokine TNFalpha mRNA but not IL-6 or IL-1alpha mRNA. To determine if K5-PKCalpha mice display an altered response to TPA-promotion, 7, 12-dimethylbenz[a]anthracene-initiated K5-PKCalpha mice and wild-type mice were promoted with TPA. No differences in papilloma incidence or multiplicity were observed between K5-PKCalpha mice and wild-type littermates. These results demonstrate that the overexpression of PKCalpha in epidermis increases the expression of specific proinflammatory mediators and induces cutaneous inflammation but has little to no effect on epidermal differentiation, proliferation or TPA tumor promotion.

Differential Protein Expression in the Epidermis of Wild-Type and COX-2 Transgenic Mice

2006 ◽  
Vol 19 (2) ◽  
pp. 89-94 ◽  
Author(s):  
K. Müller-Decker ◽  
G. Fürstenberger ◽  
M. Neumann ◽  
M. Schnölzer
Keyword(s):  
Transgenic Mice ◽  
Protein Expression ◽  
Wild Type ◽  
Differential Protein Expression ◽  
Differential Protein ◽  
Cox 2

scholarly journals Relation of the induction of epidermal ornithine decarboxylase and hyperplasia to the different skin tumor-promotion susceptibilities of protein kinase C?, -? and -? transgenic mice

2001 ◽  
Vol 93 (5) ◽  
pp. 635-643 ◽  
Author(s):  
Aaron P. Jansen ◽  
Nancy E. Dreckschmidt ◽  
Eric G. Verwiebe ◽  
Deric L. Wheeler ◽  
Terry D. Oberley ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Transgenic Mice ◽  
Ornithine Decarboxylase ◽  
Tumor Promotion ◽  
Skin Tumor ◽  
Kinase C

scholarly journals Increased expression of keratin 16 causes anomalies in cytoarchitecture and keratinization in transgenic mouse skin.

1994 ◽  
Vol 127 (2) ◽  
pp. 505-520 ◽  
Author(s):  
K Takahashi ◽  
J Folmer ◽  
P A Coulombe
Keyword(s):  
Transgenic Mouse ◽  
Mouse Skin ◽  
Ultrastructural Level ◽  
Wild Type ◽  
Wound Edge ◽  
Outer Root Sheath ◽  
Keratin 16 ◽  
Keratin Expression ◽  
Root Sheath ◽  
Keratin Filaments

Injury to epidermis and other stratified epithelia triggers profound but transient changes in the pattern of keratin expression. In postmitotic cells located at the wound edge, a strong induction of K6, K16, and K17 synthesis occurs at the expense of the keratins produced under the normal situation. The functional significance of these alterations in keratin expression is not known. Here, we report that overexpression of a wild-type human K16 gene in a tissue-specific fashion in transgenic mice causes aberrant keratinization of the hair follicle outer root sheath and proximal epidermis, and it leads to hyperproliferation and increased thickness of the living layers (acanthosis), as well as cornified layers (hyperkeratosis). The pathogenesis of lesions in transgenic mouse skin begins with a reorganization of keratin filaments in postmitotic keratinocytes, and it progresses in a transgene level-dependent fashion to include disruption of keratinocyte cytoarchitecture and structural alterations in desmosomes at the cell surface. No evidence of cell lysis could be found at the ultrastructural level. These results demonstrate that the disruption of the normal keratin profile caused by increased K16 expression interferes with the program of terminal differentiation in outer root sheath and epidermis. They further suggest that when present at sufficiently high intracellular levels, K16, along with K6 and K17, appear capable of inducing a reorganization of keratin filaments in the cytoplasm of skin epithelial cells.

scholarly journals Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice

2011 ◽  
Vol 10 (1) ◽  
pp. 149 ◽  
Author(s):  
Kristoffer W Brudvik ◽  
Jan E Paulsen ◽  
Einar M Aandahl ◽  
Borghild Roald ◽  
Kjetil Taskén
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Nuclear Translocation ◽  
Tumor Promotion ◽  
Cox 2 ◽  
Kinase A

scholarly journals Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis

2007 ◽  
Vol 292 (1) ◽  
pp. C24-C32 ◽  
Author(s):  
Elizabeth V. Wattenberg
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Mouse Skin ◽  
Tumor Promotion ◽  
Skin Tumor ◽  
Tumor Promoter ◽  
Kinase C ◽  
And Function

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na+,K+-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

scholarly journals Cardiac Gsα overexpression enhances L-type calcium channels through an adenylyl cyclase independent pathway

1998 ◽  
Vol 95 (16) ◽  
pp. 9669-9674 ◽  
Author(s):  
Alan S. Lader ◽  
Yong-Fu Xiao ◽  
Yoshihiro Ishikawa ◽  
Yanning Cui ◽  
Dorothy E. Vatner ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transgenic Mice ◽  
Protein Kinase A ◽  
Adenylyl Cyclase ◽  
Cardiac Myocytes ◽  
Receptor Activation ◽  
Wild Type ◽  
Α Subunit ◽  
Kinase A

The α subunit of the stimulatory heterotrimeric G protein (Gsα) is critical for the β-adrenergic receptor activation of the cAMP messenger system. The role of Gsα in regulating cardiac Ca2+ channel activity, however, remains controversial. Cultured neonatal cardiac myocytes from transgenic mice overexpressing cardiac Gsα were used to assess the role of Gsα on the whole-cell Ca2+ currents (ICa). Cardiac myocytes from transgenic mice had a 490% higher peak ICa compared with those of either wild-type controls or Gsα-nonexpressing littermates. The effect of Gsα overexpression was mimicked by intracellular dialysis of wild-type cardiac myocytes with GTPγS-activated Gsα. This effect was not mediated by protein kinase A activation as intracellular perfusion with a protein kinase A inhibitor rendered the same degree of activation in either transgenic or wild-type myocytes also dialyzed with activated Gsα. The data indicate that Gsα overexpression is associated with a constitutive enhancement of ICa which is independent of the cAMP pathway and activation of endogenous adenylyl cyclase.

scholarly journals Protein kinase D mediates synergistic expression of COX-2 induced by TNF-α and bradykinin in human colonic myofibroblasts

2009 ◽  
Vol 297 (6) ◽  
pp. C1576-C1587 ◽  
Author(s):  
James Yoo ◽  
Christine Chung ◽  
Lee Slice ◽  
James Sinnett-Smith ◽  
Enrique Rozengurt
Keyword(s):  
Protein Kinase ◽  
Critical Role ◽  
Protein Kinase D ◽  
Detectable Effect ◽  
Prostaglandin E ◽  
Inflammatory Microenvironment ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Hoe 140 ◽  
Cox 2

Myofibroblasts have recently been identified as major mediators of tumor necrosis factor-α (TNF-α)-associated colitis, but the precise mechanism(s) involved remains incompletely understood. In particular, the possibility that TNF-α signaling cross talks with other proinflammatory mediators, including bradykinin (BK), has not been examined in these cells. Here we show that treatment of 18Co cells, a model of human colonic myofibroblasts, with BK and TNF-α induced striking synergistic COX-2 protein expression that was paralleled by increases in the levels of transcripts encoding COX-2 and microsomal prostaglandin E synthase 1 (mPGES-1) and by the production of PGE2. COX-2 expression in 18Co cells treated with BK and TNF-α was prevented by the B2 BK receptor antagonist HOE-140, the preferential protein kinase C (PKC) inhibitors Ro31-8220 and GF-109203X, and Gö-6976, an inhibitor of conventional PKCs and protein kinase D (PKD). In a parallel fashion, TNF-α, while having no detectable effect on the activation of PKD when added alone, augmented PKD activation induced by BK, as measured by PKD phosphorylation at its activation loop (Ser744) and autophosphorylation site (Ser916). BK-induced PKD activation was also inhibited by HOE-140, Ro31-8220, and Gö-6976. Transfection of 18Co cells with small interfering RNA targeting PKD completely inhibited the synergistic increase in COX-2 protein in response to BK and TNF-α, demonstrating, for the first time, a critical role of PKD in the pathways leading to synergistic expression of COX-2. Our results imply that cross talk between TNF-α and BK amplifies a PKD phosphorylation cascade that mediates synergistic COX-2 expression in colonic myofibroblasts. It is plausible that PKD increases COX-2 expression in colonic myofibroblasts to promote an inflammatory microenvironment that supports tumor growth.

Inhibitory effects of oligonol on phorbol ester-induced tumor promotion and COX-2 expression in mouse skin: NF-κB and C/EBP as potential targets

2009 ◽  
Vol 273 (1) ◽  
pp. 86-97 ◽  
Author(s):  
Joydeb Kumar Kundu ◽  
Dal-Mi Hwang ◽  
Jung-Chul Lee ◽  
Eun-Jin Chang ◽  
Young Kee Shin ◽  
...  
Keyword(s):  
Phorbol Ester ◽  
Mouse Skin ◽  
Tumor Promotion ◽  
Inhibitory Effects ◽  
Cox 2
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