Molecular determinants of Akt-induced keratinocyte transformation

Segrelles, Carmen; Moral, Marta; Lara, M. Fernanda; Ruíz, Sergio; Santos, Mirentxu; Leis, Hugo; García‐Escudero, Ramón; Martínez-Cruz, Ana Belén; Martínez-Palacio, Jesús; Hernández, Pilar; Ballestı́n, Claudio; Paramio, Jesús M.

doi:10.1038/sj.onc.1209155

Cited by 82 publications

(95 citation statements)

References 78 publications

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“…We next wanted to determine whether DNp63a and constitutively active Akt (CA-Akt) had a synergistic effect on reduction of PTEN levels. 10 DNp63a alone led to a dramatic reduction in PTEN expression, while CA-Akt alone led to a modest decrease in PTEN (Figure 4c). Co-expression of DNp63a and CA-Akt led to an enhancement of DNp63a, and PTEN was further reduced as compared with CA-Akt alone (Figure 4c).…”

Section: Resultsmentioning

confidence: 99%

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ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

et al. 2011

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DNp63a, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether DNp63a regulates PTEN expression. Knockdown of DNp63a led to increases in PTEN levels and loss of activated Akt, while overexpression of DNp63a decreased PTEN levels and elevated active Akt. The repression of PTEN by DNp63a occurs independently of p53 status, as loss of DNp63a increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of DNp63a resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where DNp63a expression is highest. Additionally, we show that in keratinocytes a balance between DNp63a and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased DNp63a levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that DNp63a negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and DNp63a, which has an integral role in skin cancer development. Cell Death and Differentiation (2011) 18, 1924-1933 doi:10.1038/cdd.2011; published online 3 June 2011The p53 transcription factor family consists of the tumor suppressor p53 and the homologous p63 and p73. Unlike p53, p63 is essential for normal epidermal stratification and the proliferative potential of the epithelial stem cells. 1,2 p63 exists as various isoforms with contrasting functions. 2 The TA isoforms (TAp63a, TAp63b and TAp63g) have a full-length N-terminal transactivation domain, whereas the DN isoforms (DNp63a, DNp63b and DNp63g) have a short but distinct transactivation domain. All isoforms have a DNA-binding domain that shares high homology with p53 that allows p63 proteins to bind to p53 DNA-binding sites. 3,4 Similar to p53, the TA isoforms of p63 and p73 can promote apoptosis and growth arrest through the induction of antiproliferative genes. In contrast, the DN isoforms have been shown to induce pro-survival genes and inhibit anti-proliferative genes. [4][5][6] Several studies indicate that DNp63a, the predominant isoform in adult tissue, may function as an oncogene as it can exert a dominant-negative effect over p53 and the TAp63 and TAp73 isoforms. 2 Additionally, DNp63a is frequently overexpressed in a variety of squamous cell (SCC) and basal cell carcinomas (BCCs). 7,8 The survival factor Akt can increase DNp63a levels and in turn, DNp63a protects against UV-B-induced apoptosis via Akt activation. 9,10 However, the mechanism behind the positive feedback loop between DNp63a and Akt has not been described. Akt activation can be negated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate, thereby...

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Section: Resultsmentioning

confidence: 99%

“…7,8 The survival factor Akt can increase DNp63a levels and in turn, DNp63a protects against UV-B-induced apoptosis via Akt activation. 9,10 However, the mechanism behind the positive feedback loop between DNp63a and Akt has not been described. Akt activation can be negated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN).…”

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confidence: 99%

ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

et al. 2011

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“…Akt activity is sufficient to induce skin tumors in vivo (47)(48)(49)(50)(51), and Akt activity is increased during SCC progression initiated by chemical carcinogenesis (54). Akt pathway activation was detected by p-Akt in the suprabasal cells of epithelial cysts and was found in remnant follicular structures within SCCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

166

158

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The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli. mouse models of cancer | tumor initiating cells | epidermal stem cells S quamous cell carcinoma (SCC), a common type of nonmelanoma skin cancer, harbors significant risk of metastasis that can eventually lead to death (1). Permanent treatment and prevention of SCC requires an improved understanding of the unique cell types capable of initiating these malignancies and the mechanisms that underlie their transformation. Mutations in the Ras gene family are found in 30% of all human cancers and are often found in human cases of SCC (2-4). Numerous animal studies have extended the understanding of SCC by demonstrating a causative role for the Ras family in the development of SCC. In these mouse models, Ras signaling has been shown to be sufficient to drive epidermal tumorigenesis through either overexpression or targeted expression of an oncogenic form of Hras or Kras. These studies have targeted broad epidermal cell populations that include stem cells (SCs), as well as cells of the outer root sheath (ORS) and interfollicular epidermis (IFE) (4-9). Among these, a landmark article indicated that the SCC cells of origin reside in the hair follicle rather than the IFE (5). However, the keratin promoter used to drive oncogenic Ras expression did not allow for a direct determination of the cancer cell of origin amongst the different cell types in the hair follicle. The candidates for an SCC cell of origin therefore remained follicular SCs, ORS cells, transit amplifying (TA) cells in the matrix, and the differentiated cells of the inner root sheath (IRS) and hair shaft. In addition, other studies have shown that lineagerestricted or differentiated cells of the IFE are sufficient to serve as cancer cells of origin when subjected to supraphysiological levels of Ras activity at sites of mechanical stress (10). These high levels of Ras expression, however, are not normally found in human cases of SCC (10, 11). Between follicular SCs and TA cells, it is not clear whether one or both are capable of initiating tumorigenesis. Thus, we sought to directly compare the malignancy potential between follicular ...

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“…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

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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

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Molecular determinants of Akt-induced keratinocyte transformation

Cited by 82 publications

References 78 publications

ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

Defining the origins of Ras/p53-mediated squamous cell carcinoma

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

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