Cyclin D1 Is Transcriptionally Regulated by and Required for Transformation by Activated Signal Transducer and Activator of Transcription 3

Leslie, Kenneth; Lang, Cynthia; Devgan, Geeta; Azare, Janeen; Berishaj, Marjan; Gerald, William L.; Kim, Young Bae; Paz, Keren; Darnell, James; Albanese, Christopher; Sakamaki, Toshiyuki; Pestell, Richard G.; Bromberg, Jacqueline

doi:10.1158/0008-5472.can-05-2203

Cited by 231 publications

(190 citation statements)

References 53 publications

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“…Consistent with oncogenic alterations in the skin, activated Stat3 levels also were increased, resulting in an increased expression of cyclin D1 (Fig. 4), a transcriptional target of STAT3 (56). We recently reported that acquisition of GRIM-19 mutations or loss of its expression in primary human tumors unleashes STAT3 activity and up-regulation of cyclin D1 (16).…”

Section: Discussionsupporting

confidence: 63%

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Kalakonda¹,

Nallar²,

Jaber

et al. 2013

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

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Significance Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19) is an interferon-retinoid–regulated growth suppressor that inhibits cell growth by targeting the transcription factor STAT3 for inhibition. In primary human tumors GRIM-19 is suppressed or mutated, leading to constitutive STAT3 activity and indicating the tumor-suppressive function of GRIM-19. To understand the in vivo role of Grim-19 in tumor development, we generated a Grim-19 conditional knockout mouse. We found that deletion of even a single Grim-19 allele is sufficient to augment skin tumorigenesis in mice, thus establishing a critical role for Grim-19 as a tumor suppressor. Tumors that developed in the absence of Grim-19 exhibited mitochondrial respiratory chain dysfunction, elevated glycolysis, and Stat3-responsive gene expression.

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Section: Discussionsupporting

confidence: 63%

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Kalakonda¹,

Nallar²,

Jaber

et al. 2013

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

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“…In order to further verify the effects of TPA and ATRA on Stat3 activity, we determined the expression of cyclin D1 and survivin, two known transcriptional targets of Stat3 that regulate proliferation and cell survival, respectively (36,37). Cotreatment with ATRA and TPA resulted in lower expression levels of both of these proteins compared with TPA treatment alone in both tumors and skin, and a similar result was also observed for another proliferation marker, PCNA ( Fig.…”

Section: Atra Suppresses Stat3 Signaling In K5stat3c Micementioning

confidence: 58%

All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

Syed

Cheepala

Gill

et al. 2009

Cancer Prevention Research

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Squamous cell carcinoma (SCC) of the skin is the most clinically aggressive form of nonmelanoma skin cancer. We have determined the effects of all-trans retinoic acid (ATRA), a naturally occurring chemopreventive retinoid, on signal transducer and activator of transcription 3 (Stat3) signaling during the development of skin SCC. Stat3 is a transcription factor that plays a critical role in cell proliferation and survival, and it is constitutively active in several malignant cell types. We have previously shown that Stat3 is required for the initiation, promotion, and progression of skin SCC. ATRA is a highly efficient suppressor of tumor formation in the two-stage mouse skin carcinogenesis model and we have shown that this effect correlates with the suppression of the B-Raf/Mek/Erk signaling pathway. In this study, we have determined the pattern of Stat3 phosphorylation throughout the course of the two-stage protocol, both in the presence and absence of ATRA. We have used both SENCAR mice and K5.Stat3C transgenic mice, which express the Stat3C protein, a constitutively active form of Stat3, in the skin. Using Western blotting and immunohistochemical staining with phosphospecific antibodies, we show that coadministration of ATRA suppressed the 12-O-tetradecanoylphorbol-13-acetate-induced phosphorylation of Stat3 in both models, but was only able to suppress tumor formation in the SENCAR mice. Surprisingly, ATRA actually enhanced tumor formation in 12-O-tetradecanoylphorbol-13-acetatetreated K5.Stat3C mice. We hypothesize that ATRA blocks tumor formation, at least in part, by targeting events upstream of Stat3, such as the B-Raf/Mek/Erk pathway, and that in the K5.Stat3C mice, in which Stat3 activity is constitutive, it cannot suppress tumor formation.Nonmelanoma skin cancer is the most common cancer in the United States, with over a million new cases of the two most common forms, squamous cell carcinoma (SCC) and basal cell carcinoma, anticipated annually (1). The more clinically aggressive form is SCC (2), which has been increasing in incidence since the 1960s at annual rates from 4% to as much as 10% in recent years. Advanced disease-related and treatment-related morbidity have a profound effect on the patients' quality of life. Unlike basal cell carcinoma, which bears a single genetic hallmark of disruption of the patched-sonic hedgehog signaling pathway, the genetic alterations leading to SCC seem more complex and varied, and are poorly understood (3). Better control of advanced skin SCC is clearly necessary, and will be greatly helped by improving our understanding of the molecular basis for skin carcinogenesis and of the action of chemopreventive drugs.The two-stage mouse skin chemical carcinogenesis model is one of the best studied and most informative with regard to understanding molecular mechanisms and the evolution of cancer cells (4). It has proven to be ideal for the study of events leading to the transition from initiation, to promotion, and then progression to carcinoma. Molecular analysis ...

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“…10 We used 2 mice of each genotype for hepatocyte culture, and performed the experiments in duplicate. The data are expressed as percentages derived from the following formula: (percent) ϫ (count per minute [cpm] value of specific interferon [IFN]-␥ control/cpm value from untreated cells).…”

Section: [ 3 H]thymidine Incorporationmentioning

confidence: 99%

“…Because Stat1 activation had been linked to impaired liver regeneration, 10 PHx was also performed on Stat1 Ϫ/Ϫ ; Stat5 fl/fl; Alb-Cre and Stat1 Ϫ/Ϫ ; Stat5 fl/fl mice, and hepatocyte proliferation was analyzed after 40 hours. No differences were observed between Stat5 mutant and control mice, when Stat1 was absent (Fig.…”

Section: Delayed Liver Regenerationmentioning

confidence: 99%

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration

et al. 2007

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Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1 ؊/؊ mice with a hepatocyte-specific deletion of Stat5. Mouse genetics has been employed to dissect the degree to which GH signals through its downstream mediators Stat5 and IGF-1. Inactivation of the GHR gene results in severe postnatal growth retardation, greatly decreased levels of IGF-1, and elevated levels of circulating GH. 1,2 The transcription factors Stat5a and Stat5b are highly conserved and serve overlapping and mostly redundant roles. However, pubertal growth of Stat5b Ϫ/Ϫ males, but not females, is reduced. 3,4 In contrast, normal body growth was observed in both Stat5a Ϫ/Ϫ males and females. 4,5 The complete deletion of the entire Stat5a/b locus resulted in perinatal lethality, 6 suggesting that Stat5 has a more important role than previously considered.It can be hypothesized that the loss of Stat5 will alter the physiology of a cell, because it also controls the transcription of genes encoding suppressor of cytokine signaling 2 (SOCS2) and SOCS3, which are negative regulators of cytokine signaling. Moreover, loss of Stat5 would result in vacant recruitment sites on receptors, which could lead to the activation of other STATs and their downstream targets. To further explore the complexity of the GHStat5 regulatory network in liver, we deleted the Stat5 locus specifically in hepatocytes using Cre-mediated re-

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Cyclin D1 Is Transcriptionally Regulated by and Required for Transformation by Activated Signal Transducer and Activator of Transcription 3

Cited by 231 publications

References 53 publications

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration

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