Publications by authors named "Clay E S Comstock"

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.

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Molecular understanding of how prostate cancers evade hormone therapy greatly increased over the last several years, and the realization that de novo steroidogenesis plays a significant role in tumor progression and therapeutic bypass has led to development of promising new therapeutics. In the April 2013 issue of Endocrine-Related Cancer, Lubik et al. revealed a new molecular pathway by which the IGF2 can ignite the de novo steroidogenesis engine and promote molecular events associated with tumor progression.

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Article Synopsis
  • BAF57, a protein linked with chromatin remodeling, contributes to prostate cancer progression by altering androgen receptor activity, particularly in advanced stages like castration-resistant prostate cancer and metastasis.
  • In experiments, higher levels of BAF57 were correlated with more aggressive tumor grades, leading to changes in gene expression that bypass normal androgen signaling and enhance traits associated with cancer spread.
  • The study highlights BAF57's role in promoting metastasis through the upregulation of proteins like α2 integrin, suggesting it could serve as a potential biomarker for advanced prostate cancer.
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D-type cyclins regulate cellular outcomes in part through cyclin-dependent, kinase-independent mechanisms that modify transcription factor action, and recent in vivo studies showed that cyclin D1 associates with a large number of transcriptional regulators in cells of the retina and breast. Given the frequency of cyclin D1 alterations in cancer, it is imperative to delineate the molecular mechanisms by which cyclin D1 controls key transcription factor networks in human disease. Prostate cancer was used as a paradigm because this tumor type is reliant at all stages of the disease on androgen receptor (AR) signaling, and cyclin D1 has been shown to negatively modulate AR-dependent expression of prostate-specific antigen (KLK3/PSA).

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Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control.

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The cyclin D1b oncogene arises from alternative splicing of the CCND1 transcript, and harbors markedly enhanced oncogenic functions not shared by full-length cyclin D1 (cyclin D1a). Recent studies showed that cyclin D1b is selectively induced in a subset of tissues as a function of tumorigenesis; however, the underlying mechanism(s) that control tumor-specific cyclin D1b induction remain unsolved. Here, we identify the RNA-binding protein ASF/SF2 as a critical, allele-specific, disease-relevant effector of cyclin D1b production.

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Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged.

Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas.

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Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise.

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The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligand-binding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics.

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Background: Prostatic adenocarcinomas are dependent on androgen receptor (AR) activity for growth and progression, and therapy for disseminated disease depends on ablation of AR activity. Recurrent tumors ultimately arise wherein AR has been re-activated. One mechanism of AR restoration is via somatic mutation, wherein cells containing mutant receptors become susceptible to activation by alternative ligands, including bisphenol A (BPA).

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The retinoblastoma tumor suppressor protein (RB), a critical mediator of cell cycle progression, is functionally inactivated in the majority of human cancers, including prostatic adenocarcinoma. The importance of RB tumor suppressor function in this disease is evident because 25% to 50% of prostatic adenocarcinomas harbor aberrations in RB pathway. However, no previous studies challenged the consequence of RB inactivation on tumor cell proliferation or therapeutic response.

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Prostatic adenocarcinomas are dependent on androgen receptor (AR) signaling for growth and progression, in part through the ability of AR to induce G1-S phase cell cycle transition. Hormonal therapies that inhibit AR activity are the first line of intervention for disseminated disease, and are initially quite effective; however, recurrent, incurable tumors ultimately arise with restored AR function. Given the importance of AR in governing the potentiation of this tumor type, there has been a dedicated interest in dissecting the mechanisms by which AR promotes prostate cancer proliferation and survival.

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Prostatic adenocarcinomas depend on androgen for growth and survival. First line treatment of disseminated disease exploits this dependence by specifically targeting androgen receptor function. Clinical evidence has shown that androgen receptor is reactivated in recurrent tumors despite the continuance of androgen deprivation therapy.

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Adipose tissue is an integral component within the endocrine system. Adipocytes produce numerous bioactive substances, and their dysregulation has serious pathophysiological consequences. We previously reported that human adipose tissue from several depots produces significant amounts of prolactin (PRL).

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