Dara Aisner

Telomerase regulation: not just flipping the switch

Significant research efforts have focused on the transcriptional regulation of the catalytic protein component of telomerase, hTERT (human telomerase reverse transcriptase). However, increasing evidence indicates that regulation of hTERT is complex and not as simple as just flipping a switch. Although much remains to be learned about the regulation of telomerase, generation of full-length hTERT protein is likely to be the limiting step in the formation of active telomerase. Regulation of hTERT transcription, transport to the nucleus, assembly of the telomerase holoenzyme, recruitment of telomerase to the telomere, and the role of post-translational modifications of hTERT protein are areas of intense investigation. It is hoped that shedding light on these diverse areas of telomerase regulation will allow us to manipulate telomerase activity for therapeutic purposes.

Two Inactive Fragments of the Integral RNA Cooperate To Assemble Active Telomerase with the Human Protein Catalytic Subunit (hTERT) In Vitro

ABSTRACT We have mapped the 5′ and 3′ boundaries of the region of the human telomerase RNA (hTR) that is required to produce activity with the human protein catalytic subunit (hTERT) by using in vitro assembly systems derived from rabbit reticulocyte lysates and human cell extracts. The region spanning nucleotides +33 to +325 of the 451-base hTR is the minimal sequence required to produce levels of telomerase activity that are comparable with that made with full-length hTR. Our results suggest that the sequence approximately 270 bases downstream of the template is required for efficient assembly of active telomerase in vitro; this sequence encompasses a substantially larger portion of the 3′ end of hTR than previously thought necessary. In addition, we identified two fragments of hTR (nucleotides +33 to +147 and +164 to +325) that cannot produce telomerase activity when combined separately with hTERT but can function together to assemble active telomerase. These results suggest that the minimal sequence of hTR can be divided into two sections, both of which are required for de novo assembly of active telomerase in vitro.

Cardiac involvement with human T-cell lymphotrophic virus type-1-associated adult T-cell leukemia/lymphoma: The NIH experience

Malignant cardiac involvement is rare in patients with human T cell lymphotrophic virus type-1-associated adult T cell leukemia/lymphoma (ATLL). We report a single institution experience of eight patients with pathologically documented cardiac involvement with ATLL. Pericardial effusion and tamponade, cardiac valvular infiltration, valve leaflet tumor nodules and endocardial and myocardial tumors were observed. Cardiac involvement with ATLL was most often identified post-mortem; however, three cases were diagnosed clinically. All but one of the patients had the acute or lymphomatous subtypes of ATLL and had progressed through at least one prior systemic therapy. Patients with ATLL-related cardiac disease were also found to have pulmonary involvement suggesting that this may be a sign of increased risk of cardiac involvement. One patient with the chronic form of ATLL remains alive 10 years after undergoing cardiac valve replacement.

Molecular Basis of Diseases of the Gastrointestinal Tract

Abstract Much of the progress in the understanding of gastrointestinal disorders has continued to center on the molecular underpinning of gastrointestinal neoplasia in the 21st century. First, the development of cancer in the setting of inflammatory conditions is well represented by the association of Helicobacter pylori with gastric cancer and of inflammatory bowel diseases with colorectal cancer. Second, the development of cancer in patients with hereditary predisposition syndromes has shed light not only in the mechanisms of hereditary neoplasia, but has also led to major progress in the understanding of the molecular basis of the more common forms of sporadic cancer. The molecular characterization of the steps of gastrointestinal neoplastic development and progression has led to advances in disease diagnosis and treatment and has opened the opportunity for development of more targeted approaches to cancer prevention, surveillance, and novel therapeutics. This chapter focuses on the disease processes that most clearly illustrate the concepts and advances in molecular pathology of the gastrointestinal tract. It includes neoplastic diseases associated with a background of chronic inflammation, well-characterized gastrointestinal hereditary cancer syndromes, and the so-called sporadic cancers of the gastrointestinal tract, primarily reviewing gastric and colonic carcinogenesis.

Mo1951 Sensitive Quantitative CpG Methylation Testing in Random Colonic Biopsies for Risk Assessment of Coexisting Dysplasia in Ulcerative Colitis Patients

without dysplasia, miR-193a-3p was down-regulated 1.2-fold in UCrD (p=0.7) and 1.9-fold in UCD (p=0.05). UCD samples demonstrated increased methylation compared to normal controls and UC without neoplasia. There was a linear trend with decreased expression and increased methylation across all samples. 5-AZA treatment resulted in increased pri-miR193a transcript abundance in DLD1 (2.1-fold, p= 0.002), HCT116 cells (2.2-fold, p=0.02), and LoVo cells (1.2-fold, p=0.7), without significant change in mature miR-193a-3p expression. Transfection of 20nM and 50nM of miR-193a-3p in HCT116 cells down-regulated IL17RD, but not KRAS. Discussion: The gene encoding miR-193a-3p is methylated and its expression is down-regulated in IBD-associated neoplasia, suggesting that miR-193a-3p is regulated epigenetically. We identified IL17RD, an orphan receptor that potentiates IL-17 signaling, as a novel target of miR-193a-3p. As IL-17 signaling is up-regulated in inflammation and carcinogenesis, we postulate that down-regulation of miR-193a-3p contributes to cancer development in IBD via increased IL17RD.

Chapter 19 – Molecular Basis of Diseases of the Gastrointestinal Tract

Much of the progress in the understanding of gastrointestinal disorders has continued to center on the molecular underpinning of gastrointestinal neoplasia in the 21st century. First, the development of cancer in the setting of inflammatory conditions is well represented by the association of Helicobacter pylori with gastric cancer and of inflammatory bowel diseases with colorectal cancer. Second, the development of cancer in patients with hereditary predisposition syndromes has shed light not only in the mechanisms of hereditary neoplasia, but has also led to major progress in the understanding of the molecular basis of the more common forms of sporadic cancer. The molecular characterization of the steps of gastrointestinal neoplastic development and progression has led to advances in disease diagnosis and treatment and has opened the opportunity for development of more targeted approaches to cancer prevention, surveillance, and novel therapeutics. This chapter focuses on the disease processes that most clearly illustrate the concepts and advances in molecular pathology of the gastrointestinal tract. It includes neoplastic diseases associated with a background of chronic inflammation, well-characterized gastrointestinal hereditary cancer syndromes, and the so-called sporadic cancers of the gastrointestinal tract, primarily reviewing gastric and colonic carcinogenesis.