RESUMO
Disease development requires the activation of complex multi-factor processes involving numerous long noncoding RNAs (lncRNAs), which describe non-protein-coding RNAs longer than 200 nucleotides. Emerging evidence indicates that lncRNAs act as essential regulators that perform pivotal roles in the pathogenesis and progression of human diseases. The mechanisms underlying lncRNA involvement in diverse diseases have been extensively explored, and lncRNAs are considered powerful biomarkers for clinical practice. The lncRNA noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) antisense 1 (NCK1-AS1), also known as NCK1 divergent transcript (NCK1-DT), is encoded on human chromosome 3q22.3 and produces a 27,274-base-long transcript. NCK1-AS1 has increasingly been characterized as a causative agent for multiple diseases. The abnormal expression and involvement of NCK1-AS1 in various biological processes have been associated with several diseases. Further exploration of the mechanisms through which NCK1-AS1 contributes to disease development and progression will provide a foundation for potential clinical applications of NCK1-AS1 in the diagnosis and treatment of various diseases. This review summarizes the current understanding of the various functions and mechanisms through which NCK1-AS1 contributes to various diseases and the clinical application prospects for NCK1-AS1.
Assuntos
MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/metabolismo , MicroRNAs/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão GênicaRESUMO
The small GTPase Cdc42, a member of the Rho family, regulates essential biological processes such as cytoskeleton remodeling, migration, vesicular trafficking and cell cycle. It was demonstrated that Cdc42 overactivation through different molecular strategies increases cell sensitivity to genotoxic stress and affects the phosphorylation status of DNA damage response proteins by unknown mechanisms. By using a combination of approaches including affinity purification/mass spectrometry (AP/MS) and colocalization microscopy analysis we were able to identify Cdc42EP3/Borg2 as a putative molecular effector of these molecular and cellular events that seem to be independent of cell line or DNA damage stimuli. We then investigated the influence of Cdc42EP3/Borg2 and other potential protein partners, such as the NCK and Septin2 proteins, which could mediate cellular responses to genotoxic stress under different backgrounds of Cdc42 activity. Clonogenic assays showed a reduced cell survival when ectopically expressing the Cdc42EP3/Borg2, NCK2 or Septin2 in an overactivated Cdc42-dependent background. Moreover, endogenous NCK appears to relocate into the nucleus upon Cdc42 overactivation, especially under genotoxic stress, and promotes the suppression of Chk1 phosphorylation. In sum, our findings reinforce Cdc42 as an important player involved in the DNA damage response acting through Cdc42EP3/Borg2 and NCK proteins following genomic instability conditions.