Cripto-1 Alters Keratinocyte Differentiation via Blockade of Transforming Growth Factor-β1 Signaling: Role in Skin Carcinogenesis

Shukla, Anjali; Ho, Yan; Liu, Xin; Ryscavage, Andrew; Glick, Adam B.

doi:10.1158/1541-7786.mcr-07-0396

Cited by 19 publications

(21 citation statements)

References 34 publications

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“…Consistent with this notion, Smad7 is poorly expressed in the developing epidermis and is induced in the p63-null epidermis. It has been previously reported that Smad7 induces expression of Cripto-1, and that both Smad7 and Cripto-1 induce Krt8 expression in mouse keratinocytes (21,37). Loss of p63 does not affect Cripto-1 expression, 7 suggesting that other molecules downstream of Smad7 are required for repressing non-epidermal genes.…”

Section: Discussionmentioning

confidence: 93%

p63 Suppresses Non-epidermal Lineage Markers in a Bone Morphogenetic Protein-dependent Manner via Repression of Smad7

Rosa

Antonini

Ferone

et al. 2009

Journal of Biological Chemistry

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p63, a p53 family member, plays an essential role in epidermal development by regulating its transcriptional program. Here we report a previously uncovered role of p63 in controlling bone morphogenetic protein (BMP) signaling, which is required for maintaining low expression levels of several non-epidermal genes. p63 represses transcription of the inhibitory Smad7 and activates Bmp7, thereby sustaining BMP signaling. In the absence of p63, compromised BMP signaling leads to inappropriate non-epidermal gene expression in postnatal mouse keratinocytes and in embryonic epidermis. Reactivation of BMP signaling by Smad7 knockdown and/or, to a lesser extent, by BMP treatment suppresses expression of non-epidermal genes in the absence of p63. Canonical BMP/Smad signaling is essential for control of non-epidermal genes as use of a specific inhibitor, or simultaneous knockdown of Smad1 and Smad5 counteract suppression of non-epidermal genes. Our data indicate that p63 prevents ectopic expression of non-epidermal genes by a mechanism involving Smad7 repression and, to a lesser extent, Bmp7 induction, with consequent enhancement of BMP/Smad signaling.

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Section: Discussionmentioning

confidence: 93%

p63 Suppresses Non-epidermal Lineage Markers in a Bone Morphogenetic Protein-dependent Manner via Repression of Smad7

Rosa

Antonini

Ferone

et al. 2009

Journal of Biological Chemistry

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“…ST and DT primary keratinocytes were cultured as previously described (Shukla et al, 2008) and after 3 days were infected with the c2ras retrovirus as described by Bae et al (2009). To induce TGFb1 expression, keratinocytes were cultured with 1 mg ml À1 dox for 3 days and total RNA was isolated, or culture supernatant was collected and concentrated using the Amicon Ultra-4 centrifugal device (Millipore Corp., Billerica, MA).…”

Section: Cell Culturementioning

confidence: 99%

TGFβ1-Induced Inflammation in Premalignant Epidermal Squamous Lesions Requires IL-17

Mohammed

Ryscavage

Pérez‐Lorenzo

et al. 2010

Journal of Investigative Dermatology

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Overexpression of transforming growth factor-beta1 (TGFbeta1) in the normal epidermis can provoke an inflammatory response, but whether this occurs within a developing tumor is not clear. To test this, we used an inducible transgenic mouse to overexpress TGFbeta1 in premalignant squamous lesions. Within 48 hours of TGFbeta1 induction, there was an increase in IL-17 production by both CD4(+) and gammadelta(+) T cells, together with increased expression of T-helper-17 (Th17)-polarizing cytokines. Induction of TGFbeta1 in premalignant primary keratinocytes elevated the expression of proinflammatory and Th17-polarizing cytokines, and the keratinocyte-conditioned media caused IL-17 production by naive T cells that was dependent on T-cell TGFbeta1 signaling. Microarray analysis showed significant upregulation of proinflammatory genes 2 days after TGFbeta1 induction, and this was followed by increased MPO(+), F4/80(+), and CD8(+) cells in tumors, increased CD8(+) effectors and IFNgamma(+) cells in skin-draining LNs, and tumor regression. In parallel, the percentage of tumor CD11b(+)Ly6G(+) neutrophils was reduced. Neutralization of IL-17 blocked TGFbeta1-induced CD11b(+) Ly6G(-) tumor infiltration but did not alter the reduction of neutrophils or tumor regression. Thus, TGFbeta1 overexpression causes IL-17-dependent and IL-17-independent changes in the premalignant tumor inflammatory microenvironment.

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“…Blocking the type I kinases, ALK5 (activin receptor-like kinase 5) receptor function abrogates TGFb signaling and inhibits epithelial cell morphology but stimulates smooth muscle cell differentiation in epicardial cells (Compton et al, 2006). Blocking ALK5 also inhibits keratinocyte differentiation (Shukla et al, 2008) and epithelial-mesenchymal transformation (Tojo et al, 2005). Upon activation of the receptors, both Smad and non-Smad intracellular signaling can be engaged.…”

Section: Introductionmentioning

confidence: 99%

Signaling via Alk5 controls the ontogeny of lung Clara cells

Xing

et al. 2010

Development

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SUMMARYClara cells, together with ciliated and pulmonary neuroendocrine cells, make up the epithelium of the bronchioles along the conducting airways. Clara cells are also known as progenitor or stem cells during lung regeneration after injury. The mechanisms of Clara cell differentiation are largely unknown. Transforming growth factor beta (TGFb)is a multifunctional molecule with roles in normal development and disease pathogenesis. In this study, we deleted the TGFb type I receptor Alk5 in the embryonic lung epithelium using Gata5-Cre mice. Absence of Alk5 blocked Clara cell differentiation but had no effect on ciliated or pulmonary neuroendocrine cells. Hairy/Enhancer of Split-1, which is expressed in Clara cell putative 'progenitors' was found to be a downstream target of Alk5 in vivo and in vitro. Loss of Alk5-mediated signaling also stimulated Pten gene expression and inhibited ERK phosphorylation in vivo. Using lung epithelial cells, we show that Alk5-regulated Hes1 expression is stimulated through Pten and the MEK/ERK and PI3K/AKT pathways. Thus, the signaling pathway by which TGFb/ALK5 regulates Clara cell differentiation may entail inhibition of Pten expression, which in turn activates ERK and AKT phosphorylation.

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Cripto-1 Alters Keratinocyte Differentiation via Blockade of Transforming Growth Factor-β1 Signaling: Role in Skin Carcinogenesis

Cited by 19 publications

References 34 publications

p63 Suppresses Non-epidermal Lineage Markers in a Bone Morphogenetic Protein-dependent Manner via Repression of Smad7

p63 Suppresses Non-epidermal Lineage Markers in a Bone Morphogenetic Protein-dependent Manner via Repression of Smad7

TGFβ1-Induced Inflammation in Premalignant Epidermal Squamous Lesions Requires IL-17

Signaling via Alk5 controls the ontogeny of lung Clara cells

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