Resistance of transformed mouse keratinocytes to growth inhibition by glucocorticoids

Spiegelman, Vladimir S.; Budunova, Irina; Carbajal, Steve; Slaga, Thomas J.

doi:10.1002/(sici)1098-2744(199709)20:1<99::aid-mc11>3.0.co;2-4

Cited by 18 publications

(21 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GR protein levels were compared in each sample with an internal control, vinculin (Vinc), as indicated. in this system (47,48). A progressive loss of hormone responsiveness was observed in later stages of skin cancer in this model, which was associated with both a decreased GR expression and altered GR function.…”

Section: Discussionmentioning

confidence: 72%

See 1 more Smart Citation

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Kaltreider

Davis

Lariviere

et al. 2001

Environ Health Perspect

231

131

View full text Add to dashboard Cite

Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.

show abstract

Section: Discussionmentioning

confidence: 72%

“…In the earlier stages, decreased response was associated with a decrease in expression of GR mRNA. In contrast, the later-stage tumors had normal levels of GR mRNA and protein, but the receptor was defective in signaling a hormone response even though the GR gene appeared to be intact (47,48).…”

Section: Discussionmentioning

confidence: 95%

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Kaltreider

Davis

Lariviere

et al. 2001

Environ Health Perspect

231

131

View full text Add to dashboard Cite

show abstract

“…We found previously that GR function is dramatically altered in mouse transformed keratinocytes Spiegelman et al, 1997). As a consequence, glucocorticoid hormones did not affect the growth of established papillomas nor their conversion to carcinomas (Schwarz et al, 1977;Hennings, 1987;Strawhecker and Pelling, 1992;Budunova et al, 1997).…”

Section: Introductionmentioning

confidence: 88%

“…In contrast, GR was exclusively cytoplasmic in keratinocytes in papillomas of w.t./ras+ littermates ( Figure 2b). To evaluate the function of GR in transgenic tissues, we examined the mRNA levels of the glucocorticoid-responsive gene metallothionein 1 (Mt1) , Spiegelman et al, 1997. Northern blot analysis revealed the " Figure 2 Expression and activity of GR in tumors and surrounding skin from K5-GR/ras+ and w.t./ras+ animals.…”

Section: Transgene Expressionmentioning

confidence: 99%

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

et al. 2003

View full text Add to dashboard Cite

y These authors contributed equally to the work Glucocorticoids are effective inhibitors of epidermal proliferation and skin tumorigenesis. Glucocorticoids affect cellular functions via glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated skin-targeted transgenic mice overexpressing GR under control of the keratin5 promoter (K5-GR mice). To test the hypothesis that GR plays a role as a tumor suppressor in skin, we bred K5-GR transgenic mice with Tg.AC transgenic mice, which express v-Ha-ras oncogene in the skin, and compared the susceptibility of F1 offspring to TPA-induced skin carcinogenesis. GR overexpression in the epidermis dramatically inhibited skin tumor development. In K5-GR/ras+ double transgenic mice papillomas developed later and the average number of tumors per animal was 15% (in males) and 40% (in females) of the number seen in wild type (w.t./ras+) littermates. In addition, the papillomas in w.t./ras+ animals were eight to nine times larger. GR overexpression resulted in a decrease in keratinocyte proliferation combined with a modest increase in apoptosis and differentiation of keratinocytes in K5-GR/ras+ papillomas. Our data clearly indicate that interference of GR transgenic protein with nuclear factor kappa B (NF-jB) transcription factor had resulted in NF-jB blockage in K5-GR/ras+ tumors. We discuss the role of NF-jB blockage in tumor-suppressor effect of GR.

show abstract

“…In addition, p105(sr) can serve as a potent inhibitor for RelB, which is an important player in B cell development (14). To apply p105(sr) in a specific biological context, we also tested p105(sr) in mouse skin papilloma MT1/2 cell line (31). p50 homodimer activity is significantly elevated in MT1/2 cells, and the cells are resistant to TNF␣-mediated apoptosis.…”

mentioning

confidence: 99%

A p105-based Inhibitor Broadly Represses NF-κB Activities

Kobayashi

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

An I B␣-based NF-B super repressor (sr) has been used widely for studying genes regulated by NF-B transcription factors. Repression of NF-B by I B␣(sr) also facilitates tumor necrosis factor ␣-induced apoptosis in the cell. However, I B␣ primarily targets RelA and cRel-containing complexes, leaving other NF-B/Rel protein complexes, such as p50 and p52 homodimers, and RelB heterodimers uninhibited. Because these atypical NF-B complexes also contribute to gene regulation and are activated in pathological conditions, broad inhibition of all NF-B species is of significant pharmacological and clinical interests. We have designed, generated, and tested a p105-based NF-B super repressor. We showed that p105(sr), which no longer generates p50 and undergoes signal-induced degradation, effectively inhibits all NF-B activities. In addition, we also demonstrated that p105(sr) significantly enhances tumor necrosis factor ␣-mediated killing of MT1/2 skin papilloma cells where p50 homodimer activity is elevated. Our results suggest that p105(sr) is a broader range and effective NF-B super repressor and can potentially be used in cells where a noncanonical NF-B activity is dominant or multiple NF-B activities are activated.Nuclear factor B (NF-B) 1 is a latent dimeric complex sequestered in the cytoplasm by its inhibitor I B and is activated to engage transcription in the nucleus by various stimuli (1). In normal physiological conditions such activation is transient, because of autoregulatory mechanisms (2, 3). However, this family of transcription factors is constitutively activated in many types of cancer cell and is thought to regulate anti-apoptosis factors that aid survival of the cancer cells (4 -8). Chemotherapy reagents induce death of cancer cells but also activate NF-B pathways. Therefore, activation of NF-B is a contributing factor of chemoresistance. Introduction of an I B␣-based NF-B super repressor (sr) into cancer cells has not only enhanced stimuli-induced apoptosis (9 -11) but also facilitated systematic identification of genes regulated by NF-B that may contribute to the malignancy and progression of the tumor (12). Activation of prototypic NF-B requires degradation of I Bs, and the prerequisite of the process is stimuli-induced phosphorylation of I Bs by the I B kinase-constituted signalsome (13). I B␣(sr) was generated by either mutating serine 32 and 36, which are the targets of the I B kinases or deleting the Nterminal portion of I B␣ that harbors these targets. I B␣(sr) suppresses stimuli-induced NF-B activation, because the inhibitor now cannot be phosphorylated and therefore will not be subjected to immediate degradation, and the bound NF-B subunits will not be released into the nucleus.Although in most normal and cancer cells, the NF-B activity detected is that of prototype p50/RelA heterodimer, atypical/ noncanonical NF-B species also play significant roles in gene regulations (14). For example, the RelB/p52 complex plays a key role in B cell development (14). It has also been observed that NF-B p50 h...

show abstract

Resistance of transformed mouse keratinocytes to growth inhibition by glucocorticoids

Cited by 18 publications

References 31 publications

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

A p105-based Inhibitor Broadly Represses NF-κB Activities

Contact Info

Product

Resources

About