Iron Regulatory Protein/Iron Responsive Element (IRP/IRE) system: associated diseases and new target mRNAs (PPP1R1B)

dc.contributor
Universitat Internacional de Catalunya. Departament de Ciències Bàsiques
dc.contributor.author
Celma Nos, Ferran
dc.date.accessioned
2022-09-23T15:08:50Z
dc.date.available
2022-09-23T15:08:50Z
dc.date.issued
2022-05-17
dc.identifier.uri
http://hdl.handle.net/10803/675437
dc.description.abstract
Iron is a biometal involved in many physiological processes essential for life. Regulation of both systemic and cellular iron homeostasis is crucial for health. The IRP/IRE post-transcriptional regulatory system is in charge to control iron uptake, utilization, storage and export at cellular level. There are two iron regulatory proteins (IRP1 and IRP2) which recognize and bind conserved mRNA motifs named iron responsive elements (IREs). These IREs are located in the mRNA untranslated regions (UTR) of genes involved in iron metabolism. IRP/IRE binding is produced under cellular iron depletion conditions, modifying the expression of several proteins related with cellular iron acquisition, mobilization and storage. Depending on the location of the IREs in the target mRNA, the binding of the IRPs regulates differentially its expression. When IREs are present in the 3' UTR their binding to the IRPs stabilize the mRNA, protecting it front degradation and increasing its translation. On the other hand, the translation is inhibited when IRPs bind IREs located in the 5’ UTR. IRP/IRE system missregulation leads to human diseases denoting the importance of this post-transcriptional gene regulation. As part of my thesis (objective 1) we describe new cases of patients with Hereditary Hyperferritinemia Cataract Syndrome (HHCS) with mutations in the FTL IRE (Paris1 c.-160A>G and Madrid/Philadelphia c.-167G>T mutations) and we did an exhaustive revision of all literature reported cases. A genome-wide study made by our group, in order to characterize all the mRNAs that interact with the IRPs, identified 263 mRNAs that are potential IRP-target genes (44 mRNAs bind both IRPs, 102 bind specifically IRP1 and 117 bind specifically IRP2). The objective 3 of my thesis is focused in the characterization of one of these novel IRP-target mRNAs: PPP1R1B (DARPP-32 protein). DARPP-32 is a dopaminergic neurotransmission integrator which its main function is to inhibit protein phosphatase 1 (PP1). We identified a functional 5’IRE in mouse Ppp1r1b mRNA that binds in vitro with IRP1. Further, DARPP-32 protein expression is downregulated in two human cell lines under iron deprivation by an iron chelator and upregulated with an iron source, in agreement with an IRP/IRE regulation by a 5’IRE. Finally, in my thesis objective 2, we also contributed to the characterization of a Slc11a2 IRE knock-in mouse model to dissect the Dmt1 3’ IRE function in iron homeostasis.
en_US
dc.format.extent
140 p.
en_US
dc.format.mimetype
application/pdf
dc.language.iso
eng
en_US
dc.publisher
Universitat Internacional de Catalunya
dc.rights.license
ADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Metabolismo del hierro
en_US
dc.subject
IRP/IRE
en_US
dc.subject
PPP1R1B
en_US
dc.subject
Iron
en_US
dc.subject
HHCS
en_US
dc.subject.other
Medicina
en_US
dc.title
Iron Regulatory Protein/Iron Responsive Element (IRP/IRE) system: associated diseases and new target mRNAs (PPP1R1B)
en_US
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
61
en_US
dc.contributor.director
Sánchez Fernández, Mayka
dc.contributor.director
Hernández Viedma, Gonzalo
dc.embargo.terms
cap
en_US
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


Documents

Tesis Ferran Celma.pdf

9.987Mb PDF

This item appears in the following Collection(s)