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1.
Plast Reconstr Surg Glob Open ; 12(5): e5796, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38706470

RESUMO

This report describes a recurrent sclerodermiform basal cell epithelioma of the malar region next to the inferior eyelid in a 57-year-old woman. Three interventions were necessary to obtain a clear margin of resection. The area of resection was closed with a local cutaneous flap. We report a rare basal cell carcinoma subtype underestimated in its aggressiveness with often inadequate medical and surgical management. This tumor, generally localized in the face, often requires aggressive surgery, and aesthetic results can be poor. The patients require close long-term follow-up even when margins are clear. General practitioners, dermatologists, and surgeons should be aware of sclerodermiform basal cell carcinoma, which is a malignant, aggressive, and recurrent tumor.

2.
Cell Death Dis ; 13(3): 204, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35246516

RESUMO

Specialized surveillance mechanisms are essential to maintain the genetic integrity of germ cells, which are not only the source of all somatic cells but also of the germ cells of the next generation. DNA damage and chromosomal aberrations are, therefore, not only detrimental for the individual but affect the entire species. In oocytes, the surveillance of the structural integrity of the DNA is maintained by the p53 family member TAp63α. The TAp63α protein is highly expressed in a closed and inactive state and gets activated to the open conformation upon the detection of DNA damage, in particular DNA double-strand breaks. To understand the cellular response to DNA damage that leads to the TAp63α triggered oocyte death we have investigated the RNA transcriptome of oocytes following irradiation at different time points. The analysis shows enhanced expression of pro-apoptotic and typical p53 target genes such as CDKn1a or Mdm2, concomitant with the activation of TAp63α. While DNA repair genes are not upregulated, inflammation-related genes become transcribed when apoptosis is initiated by activation of STAT transcription factors. Furthermore, comparison with the transcriptional profile of the ΔNp63α isoform from other studies shows only a minimal overlap, suggesting distinct regulatory programs of different p63 isoforms.


Assuntos
Transativadores , Proteína Supressora de Tumor p53 , Apoptose/genética , DNA/metabolismo , Oócitos/metabolismo , Fosfoproteínas/metabolismo , Isoformas de Proteínas/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Cell ; 176(5): 1054-1067.e12, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30773316

RESUMO

Vault RNAs (vtRNA) are small non-coding RNAs transcribed by RNA polymerase III found in many eukaryotes. Although they have been linked to drug resistance, apoptosis, and viral replication, their molecular functions remain unclear. Here, we show that vault RNAs directly bind the autophagy receptor sequestosome-1/p62 in human and murine cells. Overexpression of human vtRNA1-1 inhibits, while its antisense LNA-mediated knockdown enhances p62-dependent autophagy. Starvation of cells reduces the steady-state and p62-bound levels of vault RNA1-1 and induces autophagy. Mechanistically, p62 mutants that fail to bind vtRNAs display increased p62 homo-oligomerization and augmented interaction with autophagic effectors. Thus, vtRNA1-1 directly regulates selective autophagy by binding p62 and interference with oligomerization, a critical step of p62 function. Our data uncover a striking example of the potential of RNA to control protein functions directly, as previously recognized for protein-protein interactions and post-translational modifications.


Assuntos
Autofagia/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Células HeLa , Humanos , Camundongos , Células RAW 264.7 , RNA/metabolismo , RNA não Traduzido/metabolismo , RNA não Traduzido/fisiologia , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo
4.
Cell ; 147(3): 525-38, 2011 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-22036562

RESUMO

The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel finding that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease.


Assuntos
Brônquios/citologia , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/patologia , Pulmão/fisiologia , Alvéolos Pulmonares/citologia , Síndrome do Desconforto Respiratório/patologia , Células-Tronco/citologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Pulmão/citologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/virologia , Ratos , Fatores de Transcrição/genética , Cicatrização
6.
Cell ; 144(4): 566-76, 2011 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-21335238

RESUMO

TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ∼20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.


Assuntos
Oócitos/metabolismo , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Transativadores/química , Transativadores/metabolismo , Animais , DNA/metabolismo , Dimerização , Feminino , Raios gama , Camundongos , Modelos Moleculares , Fosforilação , Multimerização Proteica , Proteína Supressora de Tumor p53/metabolismo
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