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Dr. Maria Ruiz-Echevarria
Assistant Professor Biochemistry & Molecular Biology
B.S., Universidad de Ciencias, Granada, Spain , 1987.
Ph.D.,Centro de Investifaciones Biologicas-UAM, Madrid, Spain, 1992
Post-doctoratal Fellow, Univ. of Medicine and Dentistry of New Jersey, Piscataway, New Jersey
Adjunct Assistant Professor, Univ. of Medicine and Dentistry of New Jersey, Piscataway, New Jersey
Project Leader, CuraGen Corporation, New Haven, Connecticut.
Assistant Professor, Weill Medical College, New York, New York |
RESEARCH INTERESTS Post-transcriptional control of gene expression during differentiation and tumorigenesis - Mechanisms of tumor progression: role of transcripts containing upstream open reading frames
- Role of translational control on ES cell differentiation
- Mechanistic link between mRNA degradation and translation
Selected Publications Contact Information Faculty Page |
Cells need to integrate intrinsic and environmental information and coordinate multiple regulatory mechanisms of gene expression to properly exert biological functions. In fact, regulation of gene expression is central to most cellular processes and encompasses most of biology, from cell proliferation and differentiation to development. While studies have traditionally focused on transcription as a major regulator of gene expression, it has become apparent that the post-transcriptional control of gene expression, including processing, export, localization, decay and translation of mRNAs, may play an equally important role. |
Translational control and tumorigenesis Translational control is a key step in gene expression. Current knowledge suggests that the majority of translational control occurs at the level of initiation, thus implicating the leader region of the mRNA as one of the major sites of translation regulation. We have analyzed the leader regions of genes involved in tumor progression and noted the presence of regulatory short upstream open reading frames (uORFs) in a large number of them. Upstream ORFs in the leader regions of transcripts are among the various cis elements that can participate in post-transcriptional control of gene expression at the level of translation and indirectly regulating mRNA stability. These regulatory sequences are in fact present only 5%-10% of mRNAs, but a high percentage of these mRNAs encode genes involved in the control of cellular growth, differentiation and other essential functions for the cell, which expression must be tightly regulated. The main goal of this project is to analyze the role of these regulatory sequences in the expression of the genes involved in tumor progression and to identify the signals, factors and mechanisms that control their activation and result in establishment of an a aggressive tumor phenotype. (top) |
Stem Cell Differentiation and Post-transcriptional Control Using hematopoietic stem cells (HSC) as a model system, we have gathered evidence that regulation of lineage commitment from a pluripotent stem cell is mediated by multiple regulatory pathways that rely on translation initiation. Inhibiting translation initiation leads to a decrease in lineage commitment and a substantial increase in the numbers of pluripotent cells in embryonic stem cell models and adult hematopoietic stem cells. The findings are consistent with the concept that a population of committed progenitors is permissive for further differentiation based upon translation of critical translationally repressed transcripts. ‘Instructive signals’ (eg. cytokines, intercrines) may act by increasing translation of these transcripts either specifically or broadly and this effect may in turn trigger a whole ‘gene expression cascade’ resulting in differentiation of a specific cell type. Interestingly, a large percentage of these translationally regulated (“repressed”) transcripts have complex 5’ UTR structures with one or more upstream open reading frames (uORFs). The main goals of this project are to identify the critical transcripts which translation is necessary to trigger differentiation and to analyze how their expression is regulated and coordinated to direct specific differentiation programs. (top) |
Link between translation and mRNA degradation The presence of nonsense mutations that introduce in-frame premature translation termination codons (PTCs; UAA, UAG, UGA) not only lead to premature translation termination but also to rapid degradation of the mRNA by a RNA surveillance mechanism known as nonsense-mediated mRNA decay (NMD). This mechanism is ubiquitous among eukaryotes and protects the organism from the deleterious effects of truncated proteins that could result if nonsense-containing transcripts were stable. In fact, the severity of a disease caused by nonsense mutations depends on the reduction in the level of mRNA from the mutant allele. However, this pathway also controls the stability of selected physiological transcripts (transcripts containing uORFs, some alternatively spliced transcripts, etc) and by doing so it has broad consequences in the regulated control of gene expression. The long-term goal of our work is to understand the basic mechanism of NMD, its role as a modulator of disease and gene expression and its potential role as a therapeutic agent. (top) |
Relevance of these studies In its most general sense, our research aims to elucidate the mechanisms that integrate and coordinate the expression of multiple genes or gene networks in response to distinct cues (i.e. differentiation, apoptosis) and when appropriate utilize this information to develop strategies for therapeutic intervention. Post-transcriptional levels of regulation such as mRNA degradation and translational control are an integral part of gene expression and add substantial complexity to the mechanisms that control gene expression. Importantly, appreciation of these mechanisms will have a tremendous impact on the design of therapeutic strategies that can be applied to broad classes of human diseases. For example, it is known that deregulation of oncogenes (which often contain uORFs) lead to a pro-oncogenic phenotype. Other data suggest that some cancers are a consequence of stem cell populations which undergo a program of differentiation that define tumor phenotype -as described above, translation and uORF-containing transcripts play an important role in stem cell differentiation-. Finally, numerous diseases are consequence of the presence of nonsense mutations in relevant genes. PTC-based diseases are ideal targets for therapeutic intervention by using drugs that overcome the presence of the nonsense mutation and/or affect the stability of the mRNA. (top) |
Contact Information Assistant Professor of Biochemistry & Molecular Biology Brody 5S-32 The Brody School of Medicine at East Carolina University Greenville, NC 27834 phone: 252.744.2856 email: ruizechevarriam@ecu.edu (top) |
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