RESUMO
The p38 member of the mitogen-activated protein kinase superfamily is engaged by phosphorylation in response to environmental stress signals, and may have either permissive or inhibitor roles upon cell proliferation. The cell cycle in the proliferative zone of the retina is tightly controlled and proceeds in synchrony with interkinetic migration of the neuroblast nuclei. We examined the association of p38 kinase activity with the cell cycle in the normal, non-stressed retina of the developing rat, maintained either in vivo or in vitro. Using immunohistochemistry, we show that mitotic profiles in the developing retina are highly enriched for phosphorylated p38. Blockade of p38 activity with the chemical inhibitor SB203580 for 4 h transiently arrested cells at the metaphase-anaphase transition and induced cell death after 20 h. p38 inhibition induced an aberrant mitotic profile, with chromosomes arranged in one side of the cell. The data show that p38 is active during normal mitosis and we suggest that p38 is required for the proper cell cycle progression during metaphase-anaphase transition in retinal neuroblasts.
Assuntos
Envelhecimento/metabolismo , Animais Recém-Nascidos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mitose/fisiologia , Retina/enzimologia , Retina/crescimento & desenvolvimento , Anáfase/fisiologia , Animais , Animais Recém-Nascidos/genética , Animais Recém-Nascidos/crescimento & desenvolvimento , Ciclo Celular/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Metáfase/fisiologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/farmacologia , Ratos , Ratos Endogâmicos , Ratos Long-Evans , Valores de Referência , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Studies of programmed cell death in the developing retina in vitro are currently reviewed. The results of inhibiting protein synthesis in retinal explants indicate two mechanisms of apoptosis. One mechanism depends on the synthesis of positive modulators ('killer proteins'), while a distinct, latent mechanism appears to be continuously blocked by negative modulators. Extracellular modulators of apoptosis include the neurotrophic factors NT-4 and BDNF, while glutamate may have either a positive or a negative modulatory action on apoptosis. Several protein kinases selectively modulate apoptosis in distinct retinal layers. Calcium and nitric oxide were also shown to affect apoptosis in the developing retianl tissue. The protein c-Jun was found associated with apoptosis in various circumstances, while p53 seems to be selectively expressed in some instances of apoptosis. The results indicate that the sensitivity of each retinal cell to apoptosis is controlled by multiple, interactive, cell type- and context-specific mechanisms. Apoptosis in the retina depends on a critical interplay of extracellular signals delivered through neurotrophic factors, neurotransmitters and neuromodulators, several signal transduction pathways, and the expression of a variety of genes.