RESUMEN
Breast cancer develops upon sequential acquisition of driver mutations in mammary epithelial cells; however, how these mutations collaborate to transform normal cells remains unclear in most cases. We aimed to reconstitute this process in a particular case. To this end, we combined the activated form of the PI 3-kinase harboring the H1047R mutation with the inactivation of the histone lysine methyl-transferase KMT2D in the non-tumorigenic human mammary epithelial cell line MCF10A. We found that PI 3-kinase activation promoted cell-cycle progression, especially when growth signals were limiting, as well as cell migration, both in a collective monolayer and as single cells. Furthermore, we showed that KMT2D inactivation had relatively little influence on these processes, except for single-cell migration, which KMT2D inactivation promoted in synergy with PI 3-kinase activation. The combination of these two genetic alterations induced expression of the ARPC5L gene that encodes a subunit of the Arp2/3 complex. ARPC5L depletion fully abolished the enhanced migration persistence exhibited by double-mutant cells. Our reconstitution approach in MCF10A has thus revealed both the cell function and the single-cell migration, and the underlying Arp2/3-dependent mechanism, which are synergistically regulated when KMT2D inactivation is combined with the activation of the PI 3-kinase.
Asunto(s)
Complejo 2-3 Proteico Relacionado con la Actina , Movimiento Celular , Células Epiteliales , N-Metiltransferasa de Histona-Lisina , Fosfatidilinositol 3-Quinasas , Humanos , Movimiento Celular/genética , Células Epiteliales/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/genética , Femenino , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/citología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Mutación/genética , Línea CelularRESUMEN
Electronic vaccine certificates (EVC) for COVID-19 vaccination are likely to become widespread. Blockchain (BC) is an electronic immutable distributed ledger and is one of the more common proposed EVC platform options. However, the principles of blockchain are not widely understood by public health and medical professionals. We attempt to describe, in an accessible style, how BC works and the potential benefits and drawbacks in its use for EVCs. Our assessment is BC technology is not well suited to be used for EVCs. Overall, blockchain technology is based on two key principles: the use of cryptography, and a distributed immutable ledger in the format of blockchains. While the use of cryptography can provide ease of sharing vaccination records while maintaining privacy, EVCs require some amount of contribution from a centralized authority to confirm vaccine status; this is partly because these authorities are responsible for the distribution and often the administration of the vaccine. Having the data distributed makes the role of a centralized authority less effective. We concluded there are alternative ways to use cryptography outside of a BC that allow a centralized authority to better participate, which seems necessary for an EVC platform to be of practical use.
