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Aberrations of Notch signaling have been implicated in a variety of human cancers. Oncogenic mutations in NOTCH1 are common in human T-cell leukemia and lymphomas. However, loss-of-function somatic mutations in NOTCH1 arising in solid tumors imply a tumor suppressor function, which highlights the need to understand Notch signaling more completely. Here, we describe the small GTPase RhoE/Rnd3 as a downstream mediator of Notch signaling in squamous cell carcinomas (SCC) that arise in skin epithelia. RhoE is a transcriptional target of activated Notch1, which is attenuated broadly in SCC cells. RhoE depletion suppresses Notch1-mediated signaling in vitro, rendering primary keratinocytes resistant to Notch1-mediated differentiation and thereby favoring a proliferative cell fate. Mechanistic investigations indicated that RhoE controls a key step in Notch1 signaling by mediating nuclear translocation of the activated portion of Notch1 (N1IC) through interaction with importins. Our results define RhoE as a Notch1 target that is essential for recruitment of N1IC to the promoters of Notch1 target genes, establishing a regulatory feedback loop in Notch1 signaling. This molecular circuitry may inform distinct cell fate decisions to Notch1 in epithelial tissues, where carcinomas such as SCC arise., (©2014 AACR)

Calcineurin is the only known serine-threonine phosphatase under calcium-calmodulin control and key regulator of the immune system. Treatment of patients with calcineurin-inhibitory drugs like cyclosporin A and FK506 to prevent graft rejection dramatically increases the risk of cutaneous squamous cell carcinoma, which is a major cause of death after organ transplants. Recent evidence indicates that suppression of calcineurin signaling, together with its impact on the immune system, exerts direct tumor-promoting effects in keratinocytes, enhancing cancer stem cell potential. The underlying mechanism involves interruption of a double negative regulatory axis, whereby calcineurin and nuclear factors of activated T-cell signaling inhibits expression of ATF3, a negative regulator of p53. The resulting suppression of keratinocyte cancer cell senescence is of likely clinical significance for the many patients under treatment with calcineurin inhibitors and may be of relevance for other cancer types in which altered calcium-calcineurin signaling plays a role., (©2011 AACR.)

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibited DNA synthesis in transformed mouse keratinocytes (Pam212) in a time- and dose-dependent manner as measured by [3H]thymidine incorporation. To investigate the mechanism through which 1,25-(OH)2D3 acts, we examined its effects on Pam212 cells further transformed with the E1A oncogene. Here, we show that transformation of the cells with the E1A oncogene induced resistance to the effects of 1,25-(OH)2D3 on inhibition of growth of Pam212 cells. While 1,25-(OH)2D3 treatment increased the level of expression of vitamin D receptor mRNA 20-fold in parental cells, the E1A-transformed cells failed to express vitamin D receptor mRNA even after treatment with 1,25-(OH)2D3. Transfection of the E1A-transformed cell line with an expression construct encoding the vitamin D receptor restored receptor expression as well as the inhibition of growth by 1,25-(OH)2D3. These results suggest that one of the mechanisms for acquisition of 1,25-(OH)2D3 resistance induced by E1A may involve loss of vitamin D receptor inducibility by 1,25-(OH)2D3.

Acute treatment of mouse skin with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces marked epidermal hyperplasia, which is well evident by 24 h and maximal by 48-72 h. These effects are associated with the early induction of transforming growth factor (TGF) beta 1 expression in the epidermis. We show here that, in contrast to TGF-beta 1, TGF-beta 2, and TGF-beta 3, skin expression is significantly down-modulated in response to TPA. TGF-beta 3 RNA levels decreased by 6 h of treatment but returned to normal or even higher levels at later times. The TGF-beta 3 protein could be detected immunohistochemically in both dermis and epidermis in control skins and at early times of TPA treatment. However, at later times, TGF-beta 3 was found only in dermal cells and not in the epidermis. TGF-beta 2 RNA expression was found to be significantly down-modulated by 24 h of TPA treatment and remained low even at later times. Thus, differential control of the 3 TGF-beta isoforms appears to be a likely determinant of normal skin homeostasis and could be at least partially responsible for TPA-induced skin hyperplasia.