A cancer-associated CDKN1B mutation induces p27 phosphorylation on a novel residue: a new mechanism for tumor suppressor loss-of-function

CDKN1B haploinsufficiency promotes the development of several human cancers. The gene encodes p27Kip1 , a protein playing pivotal roles in the control of growth, differentiation, cytoskeleton dynamics and cytokinesis. CDKN1B haploinsufficiency has been associated with chromosomal or gene aberrations. However, very few data exist on the mechanisms by which CDKN1B missense mutations facilitate carcinogenesis. Here, we report a functional study on a cancer-associated germinal p27Kip1 variant, namely glycine9->arginine-p27Kip1 (G9R-p27Kip1 ) identified in a parathyroid adenoma. We unexpectedly found that G9R-p27Kip1 lacks the major tumor suppressor activities of p27Kip1 including its antiproliferative and pro-apoptotic functions. In addition, G9R-p27Kip1 transfection in cell lines induces the formation of more numerous and larger spheres when compared to wild type p27Kip1 -transfected cells. We demonstrated that the mutation creates a consensus sequence for basophilic kinases causing a massive phosphorylation of G9R-p27Kip1 on S12, a residue normally never found modified in p27Kip1 . The novel S12 phosphorylation appears responsible for the loss of function of G9R-p27Kip1 since S12AG9R-p27Kip1 recovers most of the p27Kip1 tumor suppressor activities. In addition, the expression of the phosphomimetic S12D-p27Kip1 recapitulates G9R-p27Kip1 properties. Mechanistically, S12 phosphorylation enhances the nuclear localization of the mutant protein, and also reduces its CDK2/CDK1 inhibition activity. To our knowledge, this is the first reported case of quantitative phosphorylation of a p27Kip1 variant on a physiologically unmodified residue associated with the loss of several tumor suppressor activities. In addition, our findings demonstrate that haploinsufficiency might be due to unpredictable post-translational modifications due to generation of novel consensus sequences by cancer-associated missense mutations

¿¡Ayuda!? : las representaciones de género en las publicidades de la marca Ayudín

La tesina "¿¡Ayuda?!” se sitúa dentro de las problemáticas relativas a la construcción de representaciones de género en publicidad, la desnaturalización de estereotipos y la lucha por la visibilización de la economía del cuidado. Se trata de una investigación abordada desde una perspectiva sociosemiótica, cuyo objeto de estudio son las representaciones de género en el discurso publicitario de la marca Ayudín antes y después de 2015, año de inflexión, por ser el primero en el que se realizó la marcha del “Ni una menos” en Argentina. El trabajo indaga acerca de cómo "Ayudín” -una marca mainstream dentro de la categoría “limpiadores”- retomó, en su comunicación de marca y producto, las transformaciones sociales en torno al género.¿Hubo un cambio en la estrategiacomunicacionaldelamarca?¿Varió la forma de representar a mujeres, hombres y familias en sus comerciales? ¿Hay una variación significativa en los estereotipos representacionales a partir de 2015? ¿Cómo construyen estos comerciales la representación de género? ¿Qué aspectos de la perspectiva de género toman? ¿Cuáles dejan de lado para contar esas historias y a esos personajes? ¿Qué sucede en la categoría de productos de limpieza para el hogar? Y puntualmente: ¿Cómo son las representaciones de género en los comerciales de las lavandinas marca Ayudín? La hipótesis que hila el trabajo plantea que las tensiones entre elementos emergentes y elementos dominantes, hegemónicos, en torno a la representación de género, generan un escenario tanto de transición como de tensión y reproducción de los estereotipos (en este caso puntual, en torno a mujeres, hombres, infancias y familias). El objetivo general del trabajo es comparar las representaciones de género que aparecen en los spots publicitarios de la marca Ayudín en dos momentos históricos distintos para intentar dilucidar si existen variaciones entre sí, y -si las hay- identificar de qué tipo son. En otras palabras, dar cuenta de si hay un cambio significativo en la representación de género en la estrategia publicitaria de la marca Ayudín. En cuanto a lo metodológico, el diseño de la investigación contempla el abordaje descriptivo y cualitativo del corpus de spots seleccionados, que se analiza desde una perspectiva semiocultural para comparar dos momentos distintos, a saber: de 1989 a 2015 y de 2015 a 2020. A partir de marcas en el discurso publicitario, se buscan reconstruir las posibles variaciones en las representaciones y estereotipos de género En su conjunto, esta mirada diacrónica sobre el corpus apunta a reconstruir un proceso.Fil: Barone, Clementina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Buenos Aires, Argentin

High Dosage Lithium Treatment Induces DNA Damage and p57Kip2 Decrease

Lithium salt is the first-line therapeutic option for bipolar disorder and has been proposed as a potential antitumoral drug. The effects of LiCl treatment were investigated in SH-SY5Y, a human neuroblastoma cell line and an in vitro model of dopaminergic neuronal differentiation. LiCl, at the dosage used in psychiatric treatment, does not affect cell proliferation, while at higher doses it delays the SH-SY5Y cell division cycle and for prolonged usage reduces cell viability. Moreover, the ion treatment affects DNA integrity as demonstrated by accumulation of p53 and γH2AX (the phosphorylated form of H2AX histone), two important markers of genome damage. p57Kip2, a CIP/Kip protein, is required for proper neuronal maturation and represents a main factor of response to stress including genotoxicity. We evaluated the effect of lithium on p57Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57Kip2 content handling, confirmed that the CKI/Kip reduction plays a key role in the DNA damage activated by lithium and suggests the unanticipated view that p57Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair

Case Report: Sequential postzygotic HRAS mutation and gains of the paternal chromosome 11 carrying the mutated allele in a patient with epidermal nevus and rhabdomyosarcoma: evidence of a multiple-hit mechanism involving HRAS in oncogenic transformation

We report a 7-year-old boy born with epidermal nevi (EN) arranged according to Blaschko's lines involving the face and head, right upper limb, chest, and left lower limb, who developed a left paratesticular embryonal rhabdomyosarcoma at 18 months of age. Parallel sequencing identified a gain-of-function variant (c.37G>C, p.Gly13Arg) of HRAS in both epidermal nevus and tumor but not in leukocytes or buccal mucosal epithelial cells, indicating its postzygotic origin. The variant accounted for 33% and 92% of the total reads in the nevus and tumor DNA specimens, respectively, supporting additional somatic hits in the latter. DNA methylation (DNAm) profiling of the tumor documented a signature consistent with embryonal rhabdomyosarcoma and CNV array analysis inferred from the DNAm arrays and subsequent MLPA analysis demonstrated copy number gains of the entire paternal chromosome 11 carrying the mutated HRAS allele, likely as the result of paternal unidisomy followed by subsequent gain(s) of the paternal chromosome in the tumor. Other structural rearrangements were observed in the tumours, while no additional pathogenic variants affecting genes with role in the RAS-MAPK and PI3K-AKT-MTOR pathways were identified. Our findings provide further evidence of the contribution of "gene dosage" to the multistep process driving cell transformation associated with hyperactive HRAS function