Person:
Rodríguez Escudero, María Isabel

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First Name
María Isabel
Last Name
Rodríguez Escudero
URI
https://hdl.handle.net/20.500.14352/77769
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Microbiología y Parasitología
Area
Microbiología
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2018 - 201912020 - 20211
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Author: Amo, Laura ×

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Now showing 1 - 2 of 2
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    A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons
    (Human mutation, 2021) Luna, Sandra; Torices, Leire; Mingo, Janire; Amo, Laura; Ruiz‐Ibarlucea, Pablo; Erramuzpe, Asier; Cortés, Jesús M.; Tejada, María I.; Nunes‐Xavier, Caroline E.; López, José I.; Pulido, Rafael; Rodríguez Escudero, María Isabel; Jiménez Cid, Víctor; Molina Martín, María
    The PTEN tumor suppressor gene is mutated with high incidence in tumors and in thegermline of patients with cancer predisposition or with macrocephaly associatedwith autism.PTENnonsense mutations generating premature termination codons (PTC)and producing nonfunctional truncated PTEN proteins are frequent in association withhuman disease. However, there are no studies addressing the restoration of full‐lengthPTEN proteins from the PTC‐mutatedPTENgene by translational readthrough. Here,we have performed a global translational and functional readthrough analysis of thecomplete collection ofPTENPTC somatic or hereditary mutations found in tumors or inthegermlineofpatients(disease‐associated PTEN PTCome), and we set standards forthe analysis of the potential of readthrough functional reconstitution in disease‐relevant genes. Our analysis indicates that prevalent pathogenicPTENPTC mutationsare susceptible to PTEN functional restoration in response to readthrough‐inducingcompounds. Comprehensive readthrough analyses of disease‐associated PTComes willbe valuable tools for the implementation of readthrough‐based precision interventionsin specific groups of patients
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    A pathogenic role for germline PTEN variants which accumulate into the nucleus.
    (European journal of human genetics, 2018) Mingo, Janire; Rodríguez Escudero, María Isabel; Luna, Sandra; Fernández Acero, Teresa; Amo, Laura; Jonasson, Amy R; Zori, Roberto T; López, José I; Molina, María; Cid, Víctor J.; Pulido, Rafael
    The PTEN gene encodes a master regulator protein that exerts essential functions both in the cytoplasm and in the nucleus. PTEN is mutated in the germline of both patients with heterogeneous tumor syndromic diseases, categorized as PTEN hamartoma tumor syndrome (PHTS), and a group affected with autism spectrum disorders (ASD). Previous studies have unveiled the functional heterogeneity of PTEN variants found in both patient cohorts, making functional studies necessary to provide mechanistic insights related to their pathogenicity. Here, we have functionally characterized a PTEN missense variant [c.49C>G; p.(Gln17Glu); Q17E] associated to both PHTS and ASD patients. The PTEN Q17E variant displayed partially reduced PIP3-catalytic activity and normal stability in cells, as shown using S. cerevisiae and mammalian cell experimental models. Remarkably, PTEN Q17E accumulated in the nucleus, in a process involving the PTEN N-terminal nuclear localization sequence. The analysis of additional germline-associated PTEN N-terminal variants illustrated the existence of a PTEN N-terminal region whose targeting in disease causes PTEN nuclear accumulation, in parallel with defects in PIP3-catalytic activity in cells. Our findings highlight the frequent occurrence of PTEN gene mutations targeting PTEN N-terminus whose pathogenicity may be related, at least in part, with the retention of PTEN in the nucleus. This could be important for the implementation of precision therapies for patients with alterations in the PTEN pathway.