Tesis doctoral de Mercedes Spinola Amilibia
Metastasis is a life-threatening complication of cancer that represents 90% of cancer-related deaths. It is the process by which tumor cells disseminate from the primary tumor, migrate through the basement membrane, survive in the circulatory system, invade into a secondary site, and start to proliferate. This process is mainly developed by the de-regulation of vital pathways controlling the biological mecanism. one of them is the signalling pathway that mediate the activation of the nfkb transcription factor, a central coordinator of the immune response. It has become clear that nfkb signalling has a critical role in cancer development and progression. It also regulate tumour angiogenesis and invasiveness, being correlated with up-activation of the transcription factor level. Nowadays, the mayor goal has been to determine the molecular networks, looking at genes that induce or inhibit metastasis. For this reason, we focused on two negative regulators of nfkb pathway, which are, brms1 and tax1bp1. breast cancer metastasis suppressor 1 (brms1) is a member of a functional family of genes known as metastasis suppressors that have the ability to inhibit the appearance of macroscopic metastases in breast, melanoma and ovarian tumours without affecting the growth of the primary tumour, by acting at different steps of the metastatic cascade. Very little is known about the molecular aspects of the antimetastatic properties of brms1, and therefore the structural characterization of brms1 can provide important information on the molecular mechanisms involved in this protein function. in the present study, we show the tridimensional structure of the first predicted coiled-coil motif of human brms1. In addition, it has been previously determined the participation of the n-terminal coiled-coil of this protein in interactions with some relevant proteins to cancer (rivera et al., Unpublished results). One of them is a co-factor of transcription, named nmi, n-myc and stat interactor protein. The rescued nmi fragment in a yeast to hibrid assay included the predicted coiled-coil motif. It is reported that coiled-coil regions are well known protein¿protein interaction modules (lupas, 1996), and for this reason, we selected this motif for structural sudies of the complex nmr and itc expermiments shown that the two coiled-coil motif interact upon tested conditions. on the other hand, it is reported that ubiquitination regulates at least three steps in the nfkb pathway (chen, 2005; haglun y dikic, 2005; hoeller et. Al., 2006). Tax1bp1 or «tax binding protein 1» is one of the proteins implicated in this process. The interaction between this protein and ubiquitn is through its carboxyl-terminal end, which contains two zinc finger domains (ubz) (iha et al., 2008). We obtain the tridimensional conformation of both domains, and we concluded that only ubz2 appears to be a ubiquitin binding c2h2 zinc finger domain. The consesus sequence established in the ubd (ubiquiten binding domains) is not conserved amongst ubz1 and ubz2, which suggests that the interaction with ubiquitin should take place in a different manner.
Datos académicos de la tesis doctoral «Estudios estructurales de brms1 y tax1bp1, proteinas involucradas en la via de activacion de nfkb«
- Título de la tesis: Estudios estructurales de brms1 y tax1bp1, proteinas involucradas en la via de activacion de nfkb
- Autor: Mercedes Spinola Amilibia
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 18/03/2009
Dirección y tribunal
- Director de la tesis
- Joaquin Dopazo Blázquez
- Tribunal
- Presidente del tribunal: Juan josé Aragón reyes
- Antonio Romero garrido (vocal)
- José Luis Neira falairo (vocal)
- mauricio Garcia mateu (vocal)