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Browsing by Issue Date, starting with "2023-06-12"

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  • The p53 short isoforms are activated by the integrated stress response to enhance survival in wild-type p53 cancer cell lines
    Publication . Ramalho, Ana Catarina; López-Iniesta, Maria José; Lacerda, Rafaela; Parker, Shrutee N.; Romão, Luísa; Candeias, Marco M.
    Introduction: The full-length p53 (FLp53) protein is a transcriptional factor that mediates cellular stress responses. The appropriate response is modulated according to the nature and extent of the damage, which means that p53 may promote cell cycle arrest and DNA repair or apoptosis in different situations. In all cases, p53 manages the response by modulating the expression of a wide range of target genes, as it contains two N-terminal transactivation domains. However, this gene also encodes for shorter isoforms that lack the N-terminal region and display oncogenic functions: Δ133p53 and Δ160p53. In contrast to the protective nature of the full-length protein, these two isoforms promote cell survival, proliferation and invasion. Both are typically overexpressed in tumours, while in normal tissues their levels are low or undetectable. Data from this study indicate that the elevated levels of these isoforms may be owed to the Integrated Stress Response (ISR), which is typically a pro-survival programme, and it is commonly activated in cancer cells. The ISR is initiated by a group of kinases in response to different stress stimuli, converging in the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). This blocks global translation, while promoting the expression of activating transcription factor 4 (ATF4), the main effector of ISR. Materials and Methods: In this work, cancer cell lines with endogenous p53 were used to verify the expression of its isoforms during ISR, which was induced by treatment with thapsigargin and tunicamycin. To investigate if they were translated internally, bicistronic construct systems were employed. The interaction of the isoforms with FLp53 was verified by co-immunoprecipitation and their effect on the mRNA levels of p53 target genes was evaluated. Results and discussions: The translation of Δ160p53 and Δ133p53 was promoted by ISR induction in the cell lines tested via internal translation from FLp53 mRNA. Interaction of both isoforms with FLp53 was also confirmed, and it was demonstrated that Δ160p53 selectively acts as a regulator of p53 transcriptional activity on some genes. Conclusion: These results hint at a physiological role for p53 short isoforms in the modulation of p53 target gene expression during ISR. On the other hand, their activation by abnormal ISR induction in cancer cells supports oncogenicity. The uncovering of an intersection between p53 isoforms and ISR could open a new path for future cancer therapies.
    2023-06-12Conference object Restricted access Show more
  • Parents of Children Diagnosed with Congenital Anomalies or Cerebral Palsy: Identifying Needs in Interaction with Healthcare Services
    Publication . Santos, Ana João; Braz, Paula; Folha, Teresa; Machado, Ausenda; Matias Dias, Carlos
    The changes deriving from the birth of a child with a congenital anomaly (CA) or cerebral palsy (CP) imply, in many cases, an increased interaction with health services. A cross-sectional descriptive study was conducted with a convenience sample of parents of children diagnosed with four groups of CA (severe heart anomalies, spina bifida, orofacial clefts, and Down syndrome) and/or CP. A semistructured online questionnaire to be answered by parents was sent by web link to focal points of five parent associations and professional institutions. Data were analyzed through thematic content analysis (open-ended questions) and descriptive analysis (closed-ended questions). The results indicate consistency of responses of parents of children diagnosed with different conditions, namely with respect to the perception of health services and professionals. Closed and open-ended responses indicated three main topics in the interaction between health services and parenthood: information, coordinated and integrated responses, and support. The less positive outcomes suggest unmet information needs, while positive aspects include confidence in the care provided and the “training” received from health professionals.
    2023-06-12Journal article Open access Show more