ABSTRACT
The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-κB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34(+) progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a pro-survival function of the NF-κB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Transformation, Neoplastic/metabolism , Leukemia, Myeloid, Acute/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Line, Tumor , Cell Survival , Cell Transformation, Neoplastic/genetics , Gene Expression , Gene Expression Regulation, Leukemic , Granulocytes/metabolism , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Sequestosome-1 Protein , Tretinoin/pharmacology , Ubiquitination , Up-RegulationABSTRACT
Foi estudada a relacao entre a presenca do meconio no liquido amniotico com a gasometria materno-fetal em 30 parturientes e 28 conceptos. O material estudado foi subdividido de acordo com a intensidade de meconio e nao foi demonstrada diferenca significativa entre os subgrupos quanto a gasometria materna e fetal. Por outro lado, foram observados, para o lado fetal, valores menores do pH, bem como maior de bases no subgrupo que apresentava maior intensidade de meconio. Estes achados permitiram valorizar a presenca de meconio no liquido amniotico como sinal clinico importante na avaliacao do bem-estar fetal
