Jiménez-Cervantes Frigols, Celia

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Jiménez-Cervantes Frigols, Celia

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Jiménez-Cervantes Frigols, Celia

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Universidad de Murcia. Departamento de Bioquímica y Biología Molecular"B" e Inmunología

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Open Access
Mahogunin ring finger 1 is required for genomic stability and modulates the malignant phenotype of melanoma cells.
(MDPI, 2020-10-01) Martínez-Vicente, Idoya; Abrisqueta, Marta; Bennett, Dorothy C.; Sirés-Campos, Julia; Castejón Griñán, María; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología
The mouse mahoganoid mutation abrogating Mahogunin Ring Finger‐1 (MGRN1) E3 ubiquitin ligase expression causes hyperpigmentation, congenital heart defects and neurodegeneration. To study the pathophysiology of MGRN1 loss, we compared Mgrn1‐knockout melanocytes with genetically matched controls and melan‐md1 (mahoganoid) melanocytes. MGRN1 knockout induced a more differentiated and adherent phenotype, decreased motility, increased the percentage of cells in the S phase of the cell cycle and promoted genomic instability, as shown by stronger γH2AX labelling, increased burden of DNA breaks and higher abundance of aneuploid cells. Lack of MGRN1 expression decreased the ability of melanocytes to cope with DNA breaks generated by oxidizing agents or hydroxyurea‐induced replicative stress, suggesting a contribution of genomic instability to the mahoganoid phenotype. MGRN1 knockout in B16‐F10 melanoma cells also augmented pigmentation, increased cell adhesion to collagen, impaired 2D and 3D motility and caused genomic instability. Tumors formed by Mgrn1‐KO B16‐F10 cells had lower mitotic indices, fewer Ki67‐positive cells and showed a trend towards smaller size. In short‐term lung colonization assays Mgrn1‐KO cells showed impaired colonization potential. Moreover, lower expression of MGRN1 is significantly associated with better survival of human melanoma patients. Therefore, MGRN1 might be an important phenotypic determinant of melanoma cells.
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Functional characterization of a C-terminal splice variant of the human melanocortin 1 receptor.
(Wiley, 2020-05-31) Martínez-Vicente, Idoya; Abrisqueta, Marta; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología
The melanocortin 1 receptor (MC1R) is a major determinant of skin pigmentation and sensitivity to ultraviolet radiation. When stimulated by its natural agonists, it promotes the switch from synthesis of poorly photoprotective and lightly colored pheomelanins to production of photoprotective and darker eumelanins. In addition to an unusually high number of single nucleotide polymorphisms, the MC1R is expressed as 3 protein-coding splice variants. Two transcripts display different 5’ untranslated sequences but yield the same open reading frame corresponding to the canonical 317 aminoacids protein (termed MC1R). An alternative transcript named MC1R-203 encodes for a 382 amino acids protein of poorly characterized functional properties containing an additional 65 aminoacids C-terminal extension. Given the known roles of the MC1R C-terminal extension in forward trafficking, coupling to intracellular effectors and desensitization, the different structure of this domain in MC1R and MC1R-203 may lead to significant functional alteration(s). We have assessed the functional properties of MC1R-203, as compared with the canonical MC1R form. We show that unstimulated HBL human melanoma cells express the MC1R-203 spliceoform, although at much lower levels than canonical MC1R. When expressed in heterologous HEK293 cells, the presence of the 65 aminoacid-long cytosolic extension immediately after Cys316 in MC1R-203 did not impair the intracellular stability of the protein, but it interfered with functional coupling to the cAMP cascade and with the ubiquitylation of ARRB2 associated with MC1R desensitization. Conversely, MC1R-203 retained full capacity to activate ERK1/2 signaling. Accordingly, MC1R203 displays biased signaling when expressed in HEK293 cells.
Open Access
cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT-mediated activation of protective responses to oxidative DNA damage
(Nature Publishing Group, 2018-07-05) Castejón Griñán, María; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología
Open Access
Melanoma-associated melanocortin 1 receptor variants confer redox signaling-dependent protection against oxidative DNA damage.
(Elsevier, 2024-03-26) Sánchez-Beltrán, José; Abrisqueta, Marta; Castejón Griñán, María; Cerdido Ochoa, Sonia; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Lambertos Escudero, Ana; Bioquímica y Biología Molecular B e Inmunología
Cutaneous melanoma, a lethal skin cancer, arises from malignant transformation of melanocytes. Solar ultraviolet radiation (UVR) is a major environmental risk factor for melanoma since its interaction with the skin generates DNA damage, either directly or indirectly via oxidative stress. Pheomelanin pigments exacerbate oxidative stress in melanocytes by UVR-dependent and independent mechanisms. Thus, oxidative stress is considered to contribute to melanomagenesis, particularly in people with pheomelanic pigmentation. The melanocortin 1 receptor gene (MC1R) is a major melanoma susceptibility gene. Frequent MC1R variants (varMC1R) associated with fair skin and red or yellow hair color display hypomorphic signaling to the cAMP pathway and are associated with higher melanoma risk. This association is thought to be due to production of photosensitizing pheomelanins as well as deficient induction of DNA damage repair downstream of varMC1R. However, the data on modulation of oxidative DNA damage repair by MC1R remain scarce. We recently demonstrated that varMC1R accelerates clearance of reactive oxygen species (ROS)-induced DNA strand breaks in an AKT-dependent manner. Here we show that varMC1R also protects against ROS-dependent formation of 8- oxodG, the most frequent oxidative DNA lesion. Since the base excision repair (BER) pathway mediates clearance of these DNA lesions, we analyzed induction of BER enzymes in human melanoma cells of varMC1R genotype. Agonist-mediated activation of both wildtype (wtMC1R) and varMC1R significantly induced OGG and APE-1/Ref1, the rate-limiting BER enzymes responsible for repair of 8-oxodG. Moreover, we found that NADPH oxidase (NOX)-dependent generation of ROS was responsible for AKT activation and oxidative DNA damage repair downstream of varMC1R. These observations provide a better understanding of the functional properties of melanoma-associated MC1R alleles and may be useful for the rational development of strategies to correct defective varMC1R responses for efficient photoprotection and melanoma prevention in fair-skinned individuals.
Open Access
Functional interplay between secreted ligands and receptors in melanoma.
(Academic Press Ltd-Elsevier Science Ltd, 2018-06) Sánchez-Laorden, Berta; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Bioquímica y Biología Molecular B e Inmunología
Open Access
MGRN1 as a phenotypic determinant of human melanoma cells and a potential biomarker.
(MDPI, 2022-07-26) Abrisqueta, Marta; Sánchez-Beltrán, José; Martínez-Vicente, Idoya; Sevilla, Arrate; Alonso, Santos; Boyano, María Dolores; Cerdido Ochoa, Sonia; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Lambertos Escudero, Ana; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología
Mahogunin Ring Finger 1 (MGRN1), a ubiquitin ligase expressed in melanocytes, interacts with the α melanocyte-stimulating hormone receptor, a well-known melanoma susceptibility gene. Previous studies showed that MGRN1 modulates the phenotype of mouse melanocytes and melanoma cells, with effects on pigmentation, shape, and motility. Moreover, MGRN1 knockdown augmented the burden of DNA breaks in mouse cells, indicating that loss of MGRN1 promoted genomic instability. However, data concerning the roles of MGRN1 in human melanoma cells remain scarce. We analyzed MGRN1 knockdown in human melanoma cells. Transient MGRN1 depletion with siRNA or permanent knockdown in human melanoma cells by CRISPR/Cas9 caused an apparently MITF-independent switch to a more dendritic phenotype. Lack of MGRN1 also increased the fraction of human cells in the S phase of the cell cycle and the burden of DNA breaks but did not significantly impair proliferation. Moreover, in silico analysis of publicly available melanoma datasets and estimation of MGRN1 in a cohort of clinical specimens provided preliminary evidence that MGRN1 expression is higher in human melanomas than in normal skin or nevi and pointed to an inverse correlation of MGRN1 expression in human melanoma with patient survival, thus suggesting potential use of MGRN1 as a melanoma biomarker.
Open Access
A Side-by-Side comparison of wildtype and variant melanocortin 1 receptor signaling with emphasis on protection against oxidative damage to DNA.
(MDPI, 2023-09-21) Sánchez-Beltrán, José; Abrisqueta, Marta; Padilla, Lidia; Herraiz Serrano, Cecilia María; Cerdido Ochoa, Sonia; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Lambertos Escudero, Ana; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología
Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of cAMP signaling. However, several MC1R variants show significant residual coupling to cAMP and efficiently activate mitogenic extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Yet, residual signaling and the key actions of wildtype and variant MC1R have never been assessed under strictly comparable conditions in melanocytic cells of identical genetic background. We devised a strategy based on CRISPR-Cas9 knockout of endogenous MC1R in a human melanoma cell line wildtype for BRAF, NRAS and NF1, followed by reconstitution with epitope-labeled MC1R constructs, and functional analysis of clones expressing comparable levels of wildtype, R151C or D294H MC1R. The proliferation rate, shape, adhesion, motility and sensitivity to oxidative DNA damage were compared. The R151C and D294H RHC variants displayed impaired cAMP signaling, intracellular stability similar to the wildtype, triggered ERK1/2 activation as effectively as the wildtype, and afforded partial protection against oxidative DNA damage, although less efficiently than the wildtype. Therefore, common melanoma-associated MC1R variants display biased signaling and significant genoprotective activity.
Metadata only
Isoenzimas de tirosinasa en melanocitos malignos : función de la proteina relacionada con tirosinasa 1 / Celia Jimenez-Cervantes Frigols ; directores José Carlos García-Borrón Martínez, Francisco Solano Muñoz.
(Murcia : Universidad de Murcia, Facultad de Química,, 1994) Jiménez-Cervantes Frigols, Celia
Open Access
MGRN1 depletion promotes intercellular adhesion in melanoma by upregulation of E-cadherin and inhibition of CDC42.
(Elsevier, 2023-11-25) Abrisqueta, Marta; Sánchez-Beltrán, José; Muñoz, Cristina; Castejón Griñán, María; Cerdido Ochoa, Sonia; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Lambertos Escudero, Ana; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología