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1. SHOC2 scaffold protein modulates daunorubicin-induced cell death through p53 modulation in lymphoid leukemia cells

Author

Vanessa Silva Silveira, Kleiton Silva Borges, Verena Silva Santos, Mariana Tannús Ruckert, Gabriela Maciel Vieira, Elton José Rosas Vasconcelos, Luis Fernando Peinado Nagano, Luiz Gonzaga Tone, and Carlos Alberto Scrideli

Subjects
Medicine, Science
Abstract

Abstract SHOC2 scaffold protein has been mainly related to oncogenic ERK signaling through the RAS-SHOC2-PP1 phosphatase complex. In leukemic cells however, SHOC2 upregulation has been previously related to an increased 5-year event-free survival of pediatric pre-B acute lymphoid leukemia, suggesting that SHOC2 could be a potential prognostic marker. To address such paradoxical function, our study investigated how SHOC2 impact leukemic cells drug response. Our transcriptome analysis has shown that SHOC2 can modulate the DNA-damage mediated by p53. Notably, upon genetic inhibition of SHOC2 we observed a significant impairment of p53 expression, which in turn, leads to the blockage of key apoptotic molecules. To confirm the specificity of DNA-damage related modulation, several anti-leukemic drugs has been tested and we did confirm that the proposed mechanism impairs cell death upon daunorubicin-induced DNA damage of human lymphoid cells. In conclusion, our study uncovers new insights into SHOC2 function and reveals that this scaffold protein may be essential to activate a novel mechanism of p53-induced cell death in pre-B lymphoid cells.

Published
2020
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2. SHOC2 scaffold protein modulates daunorubicin-induced cell death through p53 modulation in lymphoid leukemia cells

Author

Carlos Alberto Scrideli, Gabriela Maciel Vieira, Elton J R Vasconcelos, Verena Silva Santos, Luiz Gonzaga Tone, Vanessa da Silva Silveira, Mariana Tannús Ruckert, Kleiton Silva Borges, and Luis Fernando Peinado Nagano

Subjects
Scaffold protein, Programmed cell death, MAP Kinase Signaling System, Science, Antineoplastic Agents, Apoptosis, Article, Transcriptome, Downregulation and upregulation, Cell Line, Tumor, medicine, Leukaemia, Humans, Cancer, Haematological cancer, Multidisciplinary, Acute lymphocytic leukaemia, Chemistry, LEUCEMIA, Gene Expression Profiling, Precursor Cells, B-Lymphoid, Daunorubicin, Intracellular Signaling Peptides and Proteins, medicine.disease, Cell biology, Leukemia, Lymphoid, Gene Expression Regulation, Neoplastic, Leukemia, Cell culture, ras Proteins, Phosphatase complex, Medicine, Tumor Suppressor Protein p53, Lymphoid leukemia, DNA Damage
Abstract

SHOC2 scaffold protein has been mainly related to oncogenic ERK signaling through the RAS-SHOC2-PP1 phosphatase complex. In leukemic cells however, SHOC2 upregulation has been previously related to an increased 5-year event-free survival of pediatric pre-B acute lymphoid leukemia, suggesting that SHOC2 could be a potential prognostic marker. To address such paradoxical function, our study investigated how SHOC2 impact leukemic cells drug response. Our transcriptome analysis has shown that SHOC2 can modulate the DNA-damage mediated by p53. Notably, upon genetic inhibition of SHOC2 we observed a significant impairment of p53 expression, which in turn, leads to the blockage of key apoptotic molecules. To confirm the specificity of DNA-damage related modulation, several anti-leukemic drugs has been tested and we did confirm that the proposed mechanism impairs cell death upon daunorubicin-induced DNA damage of human lymphoid cells. In conclusion, our study uncovers new insights into SHOC2 function and reveals that this scaffold protein may be essential to activate a novel mechanism of p53-induced cell death in pre-B lymphoid cells.

Published
2020

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