RREB1 Transcription Factor Splice Variants in Urologic Cancer

Nitz, Matthew D.; Harding, Michael A.; Smith, Steven C.; Thomas, Shibu; Theodorescu, Dan

doi:10.1016/j.ajpath.2011.03.038

Cited by 20 publications

(15 citation statements)

References 36 publications

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“…Given these findings, we sought to develop a surrogate of Ral pathway status based on the fact that Ral GTPases alter gene expression through various transcription factors (18, 23, 24). Since tumors with the same levels of Ral protein but different levels of GTPase activation or effector interactions may induce such transcription factors to varying levels, which in turn might induce different clinical phenotypes, we hypothesized that Ral-dependent transcriptomic profiles might effectively capture pathway output that will be associated with salient clinicopathologic factors and outcomes.…”

Section: Resultsmentioning

confidence: 99%

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Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

et al. 2012

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RalA and RalB are small GTPases which support malignant development and progression in experimental models of bladder, prostate and squamous cancer. However, demonstration of their clinical relevance in human tumors remains lacking. Here, we developed tools to evaluate Ral protein expression, activation and transcriptional output and evaluated their association with clinicopathologic parameters in common human tumor types. In order to evaluate the relevance of Ral activation and transcriptional output, we correlated RalA and RalB activation with the mutational status of key human bladder cancer genes. We also identified and evaluated a “transcriptional signature” of genes that correlates with depletion of RalA and RalB in vivo. The Ral transcriptional signature score, but not protein expression as evaluated by immunohistochemistry, predicted disease stage, progression to muscle invasion, and survival in human bladder cancers, and metastatic and stem cell phenotypes in bladder cancer models. In prostate cancer, the Ral transcriptional signature score was associated with seminal vesicle invasion, androgen-independent progression, and reduced survival. In squamous cell carcinoma, this score was decreased in cancer tissues compared with normal mucosa, validating the experimental findings that Ral acts as a tumor-suppressor in this tumor type. Together, our findings demonstrate the clinical relevance of Ral in human cancer and provide a rationale for the development of Ral-directed therapies.

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Section: Resultsmentioning

confidence: 99%

“…We recently added the metastasis and stem-cell associated gene, CD24, to this list (13, 32), and have also implicated the RREB1 transcription factor pathway therein (18, 24). However, it bears consideration that a number of the Ral signature genes (Table 1) have been demonstrated to play important roles in bladder and other cancers.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

et al. 2012

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“…RREB1 (Ras-responsive element binding protein 1) participates in Ras signaling and cancer progression in bladder cancer [36] prostate cancer [37], and melanoma [38]. RREB1 is not known to play a role in adipose tissue, and SNPs in this gene have previously been associated with serum urate levels [39].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci

et al. 2013

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Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

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“…Given the significantly divergent effects of ATF2 splice isoform expression, future studies investigating the regulated production of these isoforms as well as their specific contributions to general and pathological biology are warranted. Studies of transcription factor splice isoform expression and function (17), particularly in pathological conditions such as cancer, have been limited (e.g., MITF/TFE transcription factors (18), RREB1 (19), STAT3 β (20), and p53 (21)). Future investigations of the splice isoforms of other key transcription factors are expected to clarify their complex and often reportedly divergent or elusive functions.…”

Section: Transcriptional and Post-transcriptional Regulation Of Atf2mentioning

confidence: 99%

ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease

Watson

Ronai

Lau

2017

Pharmacological Research

107

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Summary Stringent transcriptional regulation is crucial for normal cellular biology and organismal development. Perturbations in the proper regulation of transcription factors can result in numerous pathologies, including cancer. Thus, understanding how transcription factors are regulated and how they are dysregulated in disease states is key to the therapeutic targeting of these factors and/or the pathways that they regulate. Activating transcription factor 2 (ATF2) has been studied in a number of developmental and pathological conditions. Recent findings have shed light on the transcriptional, post-transcriptional, and post-translational regulatory mechanisms that influence ATF2 function, and thus, the transcriptional programs coordinated by ATF2. Given our current knowledge of its multiple levels of regulation and function, ATF2 represents a paradigm for the mechanistic complexity that can regulate transcription factor function. Thus, increasing our understanding of the regulation and function of ATF2 will provide insights into fundamental regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into a genomic response through transcription factors. Characterization of ATF2 dysfunction in the context of pathological conditions, particularly in cancer biology and response to therapy, will be important in understanding how pathways controlled by ATF2 or other transcription factors might be therapeutically exploited. In this review, we provide an overview of the currently known upstream regulators and downstream targets of ATF2.

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RREB1 Transcription Factor Splice Variants in Urologic Cancer

Cited by 20 publications

References 36 publications

Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci

ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease

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