Research
Our broad research interests focus on understanding the biology and molecular basis of cancer origin and progression with the goal of developing appropriate therapies. Frequently during the process of carcinogenesis the pathways that control embryonic development and tissue homeostasis are aberrantly activated. This activation contributes to the ability of the tumor cell to proliferate, evade apoptosis and metastasize. Furthermore, as it is the case during embryonic development, cellular proliferation during tumor development imposes an energetic challenge that must be carefully coordinated with metabolism.Cancer is therefore a developmental disease and understanding the molecular mechanisms that contribute to the biology of development and its link with metabolism will contribute to our understanding of tumor biology.
Our efforts have been recently focused on the receptor-ligand groups whose variable functions are mediated by transmembrane signaling events or alternatively proteolytic cleavage to generate a ligand from the receptor ectodomain. This group includes the TGFbeta receptor family, EGFR, GPCR, CD44, Notch and the TMEFF family of proteins. Specifically, our work has been focused first on the regulation and biological function of TMEFF2 and its role in prostate cancer.
The transmembrane protein with EGF and two follistatin motifs 2 (TMEFF2) is an evolutionarily conserved type I transmembrane protein expressed in the embryo and selectively in the adult brain and prostate. While it contains several domains that could potentially be important for regulating developmental pathways –i.e. TGFb and ERK—its role during development is not known. In addition, a critical role in tumorigenesis is suggested by the fact that it is up-regulated in a significant fraction of primary and metastatic prostate tumors. Several studies have suggested that TMEFF2 plays a role in suppressing the growth and invasive potential of human cancer cells while others suggest that the shed portion of TMEFF2, that lacks the cytoplasmic region, has a growth promoting activity. Our results demonstrate that the TMEFF2 tumor suppressor activity is in part due to its ability to interact with sarcosine dehydrogenase and modulate the metabolism of sarcosine, a component of the one-carbon metabolism recently identified as a marker for prostate cancer progression. In addition, we have demonstrated that the cleaved ectodomain has a distinct growth promoting effect. These observations make TMEFF2 an attractive model to study the link between cancer, development and metabolism. Using this model our research plans will focus on: (1) Analysis of the signal transduction pathways involved in prostate cancer development; (2) Identification and characterization of regulators that contribute to the aberrant activation of these pathways, including shedding regulation; (3) Understanding the influence of components of the one-carbon metabolism in prostate cancer (4) Understanding the in vivo role of TMEFF2 in cancer and in prostate development and (5) study the regulation of TMEFF2 expression and the circumstances that lead to its overexpression in prostate cancer.
Selected publications
Chen, X., Overcash, R., Green, T., Hoffman, D., Asch, A., Ruiz-Echevarria, MJ. The Tumor Suppressor Activity of the Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 (TMEFF2) Correlates with Its Ability to Modulate Sarcosine Levels. J. Biol. Chem. 2011; 286:16091-16100
Ruiz- Echevarría MJ, Munshi R, Tomback J, Goss-Kinzy T, and Peltz SW. Characterization of a General Stabilizer element that blocks deadenylation-dependent mRNA decay. J. Biol. Chem. 2001; 276:30995-31003.
Ruiz- Echevarría MJ, and Peltz, SW. The RNA binding protein Pub1 modulates the stability of transcripts containing upstream open reading frames. Cell. 2000; 101:741-751.
Gonzalez CI, Ruiz- Echevarría MJ, Vasudevan S, Henry MF and Peltz SW. The yeast hnRNP-like protein Hrp1/Nab4 marks a transcript for nonsense-mediated mRNA decay. Mol Cell. 2000; 5:489-499.
Ruiz-Echevarría MJ, Yasenchak JM, Han X, Dinman JD, and Peltz SW. The Upf3 protein is a component of the surveillance complex that monitors both translation and mRNA turnover and affects viral maintenance. PNAS. 1998; 95:8721-8726.
Czaplinsli K, Ruiz-Echevarría MJ, Weng Y, Paushkin SV, Han X, Perlick HA, Dietz HC, Ter-Avanesyan MD, and Peltz SW. Assembly of the mRNA surveillance complex occurs at a translation termination event. Genes and Development. 1998; 12:1665-1677.
Ruiz-Echevarría MJ, Gonzalez CI, and Peltz SW. Identifying the right stop: determining how the surveillance complex recognizes and degrades an aberrant mRNA. EMBO J. 1998; 17:575-589.
Ruiz-Echevarría MJ, and Peltz SW. Utilizing the GCN4 leader region to investigate the role of the sequence determinants in nonsense-mediated mRNA decay. EMBO J. 1996; 15:2810-2819.
Ruiz-Echevarría MJ, de la Cueva G, and Díaz-Orejas R. Translational coupling and limited degradation of a polycistronic messenger modulate differential gene expression in a bicistronic operon. Mol. Gen. Genet. 1995; 248:599-609.
Ruiz-Echevarría MJ, Giménez-Gallego G, and Díaz-Orejas R. Kid, a small protein of the parD stability system of plasmid R1, is an inhibitor of DNA replication acting at the DnaB level. J. Mol. Biol. 1995; 247:568-577.
Ruiz-Echevarría MJ, Berzal-Herranz A, Gerdes K, Díaz-Orejas R. The kis and kid genes of the parD maintenance system of plasmid R1 form an operon that is autorregulated at the level of transcription by the coordinated action of the Kis and Kid proteins. Mol. Microb. 1991; 5:2685-2693.
