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Tristetraprolin (TTP) is a nucleocytoplasmic 326 amino acid protein whose sequence is characterized by possessing two CCCH-type zinc finger domains. In the cytoplasm TTP function is to promote the degradation of mRNAs that contain adenylate/uridylate–rich elements (AREs). Mechanistically, TTP promotes the recruitment of poly(A)-specific deadenylases and exoribonucleases. By reducing the half-life of about 10% of all the transcripts in the cell TTP has been shown to participate in multiple cell processes that include regulation of gene expression, cell proliferation, metabolic homeostasis and control of inflammation and immune responses. However, beyond its role in mRNA decay, in the cell nucleus TTP acts as a transcriptional coregulator by interacting with chromatin modifying enzymes. TTP has been shown to repress the transactivation of NF-κB and estrogen receptor suggesting the possibility that it participates in the transcriptional regulation of hundreds of genes in human cells and its possible involvement in breast cancer progression. In this review, we discuss the cytoplasmic and nuclear functions of TTP and the effect of the dysregulation of its protein levels in the development of human diseases. We suggest that TTP be classified as a moonlighting tumor supressor protein that regulates gene expression through two different mechanims; the decay of ARE-mRNAs and a transcriptional coregulatory function.

Tesis (Doctorado en Ciencias en Biología Molecular) "Las proteínas BLR-1 y BLR-2 de Trichoderma atroviride son los homólogos de WC-1 y WC-2 de Neurospora crassa, dos factores de transcripción involucrados en la regulación de genes que responden a luz azul. BLR-1 y BLR-2 son esenciales para la fotoinducción del gen phr-1, que codifica para una fotoliasa, cuyo promotor exhibe secuencias similares elementos de respuesta a luz bien caracterizados en Neurospora, incluyendo el Elemento Albino Proximal (APE) y el Elemento de Respuesta a Luz (LRE). No obstante que phr-1 ha sido utilizado extensamente como marcador de inducción por luz azul en Trichoderma, la función de esos presuntos elementos reguladores no se ha examinado experimentalmente. El núcleo del LRE descrito en N. crassa está conformado por dos cajas GATA separadas por un número pequeño y variable de nucleótidos, a las cuales se une transitoriamente el complejo WC-1/WC-2 (WCC) tras la aplicación de un estímulo luminoso. Por medio de deleciones seriadas en el extremo 5’ del promotor de phr-1, así como por mutaciones puntuales del LRE putativo, delimitamos una región de ~50 pb que media la respuesta transcripcional a la luz azul. La región crítica para la fotorrespuesta identificada en este estudio contiene tres motivos CGATC, dos de ellos en polaridad opuesta a los sitios de unión canónicos del WCC. Los experimentos de inmunoprecipitación de cromatina mostraron que la proteína BLR-2 se encuentra unida a lo largo del promotor de phr-1 en la oscuridad, en tanto que la aplicación de un pulso de luz azul resultó en un decremento en la unión de BLR-2. Nuestros resultados sugieren que BLR-2 y probablemente BLR-1, están localizados sobre el promotor de phr-1 en la oscuridad, en una conformación propicia para llevar a cabo su función transcripcional en respuesta a la luz." "The BLR-1 and BLR-2 proteins of Trichoderma atroviride are the Neurospora crassa homologs of White Collar-1 and -2, two transcription factors involved in the regulation of genes by blue-light. BLR-1 and BLR-2 are essential for photoinduction of phr-1, a photolyase-encoding gene whose promoter exhibits sequences similar to well-characterized light regulatory elements of Neurospora, including the Albino Proximal Element (APE) and the Light Response Element (LRE). However, despite the fact that this gene has been extensively used as a blue light induction marker in Trichoderma, the function of these putative regulatory elements has not been proven. The described LRE core in N. crassa comprises two close but variably spaced GATA-boxes to which a WC-1/-2 complex binds transiently upon application of a light stimulus. Using 5´serial deletions of the phr-1 promoter, as well as point mutations of putative LREs, we were able to delimit a ~50 bp long region mediating the transcriptional response to blue-light. The identified light-responsive region contained three CGATC motifs, two of them displaying opposite polarity to canonical WCC binding sites. Chromatin immunoprecipitation experiments showed that the BLR-2 protein binds along the phr-1 promoter in darkness, whereas the application of a blue light pulse resulted in decreased BLR-2 binding to the promoter. Our results suggest that BLR-2 and probably BLR-1 are located on the phr-1 promoter in darkness ready to perform their function as transcriptional complex in response to light."