Apaf-1 is an essential factor for cytochrome c-driven caspase activation during mitochondrial apoptosis but has also an apoptosis-unrelated function. Knockdown of Apaf-1 in human cells, knockout of apaf-1 in mice, and loss-of-function mutations in the Caenorhabditis elegans apaf-1 homolog ced-4 reveal the implication of Apaf-1/CED-4 in DNA damage-induced cell-cycle arrest. Apaf-1 loss compromised the DNA damage checkpoints elicited by ionizing irradiation or chemotherapy. Apaf-1 depletion reduced the activation of the checkpoint kinase Chk1 provoked by DNA damage, and knockdown of Chk1 abrogated the Apaf-1-mediated cell-cycle arrest. Nuclear translocation of Apaf-1, induced in vitro by exogenous DNA-damaging agents, correlated in non-small cell lung cancer (NSCLC) with the endogenous activation of Chk-1, suggesting that this pathway is clinically relevant. Hence, Apaf-1 exerts two distinct, phylogenetically conserved roles in response to mitochondrial membrane permeabilization and DNA damage. These data point to a role for Apaf-1 as a bona fide tumor suppressor.
Spermine oxidase is a FAD-containing enzyme involved in polyamines catabolism, selectively oxidizing spermine to produce H2O2, spermidine, and 3-aminopropanal. Spermine oxidase is highly expressed in the mouse brain and plays a key role in regulating the levels of spermine, which is involved in protein synthesis, cell division and cell growth. Spermine is normally released by neurons at synaptic sites where it exerts a neuromodulatory function, by specifically interacting with different types of ion channels, and with ionotropic glutamate receptors. In order to get an insight into the neurobiological roles of spermine oxidase and spermine, we have deregulated spermine oxidase gene expression producing and characterizing the transgenic mouse model JoSMOrec, conditionally overexpressing the enzyme in the neocortex. We have investigated the effects of spermine oxidase overexpression in the mouse neocortex by transcript accumulation, immunohistochemical analysis, enzymatic assays and polyamine content in young and aged animals. Transgenic JoSMOrec mice showed in the neocortex a higher H2O2 production in respect to Wild-Type controls, indicating an increase of oxidative stress due to SMO overexpression. Moreover, the response of transgenic mice to excitotoxic brain injury, induced by kainic acid injection, was evaluated by analysing the behavioural phenotype, the immunodistribution of neural cell populations, and the ultrastructural features of neocortical neurons. Spermine oxidase overexpression and the consequently altered polyamine levels in the neocortex affects the cytoarchitecture in the adult and aging brain, as well as after neurotoxic insult. It resulted that the transgenic JoSMOrec mouse line is more sensitive to KA than Wild-Type mice, indicating an important role of spermine oxidase during excitotoxicity. These results provide novel evidences of the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain.
Spermine oxidase (SMO) was discovered much more recently than other enzymes involved in polyamine metabolism; this review summarizes 10 years of researches on this enzyme. Spermine oxidase (SMO) is a FAD-dependent enzyme that specifically oxidizes spermine (Spm) and plays a dominant role in the highly regulated mammalian polyamines catabolism. SMO participates in drug response, apoptosis, response to stressful stimuli and etiology of several pathological conditions, including cancer. SMO is a highly inducible enzyme, its deregulation can alter polyamine homeostasis, and dysregulation of polyamine catabolism is often associated with several disease states. The oxidative products of SMO activity are spermidine, and the reactive oxygen species H(2)O(2) and the aldehyde 3-aminopropanal each with the potential to produce cellular damages and pathologies. The SMO substrate Spm is a tetramine that plays mandatory roles in several cell functions, such as DNA synthesis, cellular proliferation, modulation of ion channels function, cellular signaling, nitric oxide synthesis and inhibition of immune responses. The goal of this review is to cover the main biochemical, cellular and physiological processes in which SMO is involved.
The retinoblastoma family of nuclear factors is composed of RB, the prototype of the tumour suppressor genes and of the strictly related genes p107 and Rb2/p130. The three genes code for proteins, namely pRb, p107 and pRb2/p130, that share similar structures and functions. These proteins are expressed, often simultaneously, in many cell types and are involved in the regulation of proliferation and differentiation. We determined the expression and the phosphorylation of the RB family gene products during the DMSO-induced differentiation of the N1E-115 murine neuroblastoma cells. In this system, pRb2/p130 was strongly up-regulated during mid-late differentiation stages, while, on the contrary, pRb and p107 resulted markedly decreased at late stages. Differentiating N1E-115 cells also showed a progressive decrease in B-myb levels, a proliferation-related protein whose constitutive expression inhibits neuronal differentiation. Transfection of each of the RB family genes in these cells was able, at different degrees, to induce neuronal differentiation, to inhibit [ 3 H]thymidine incorporation and to down-regulate the activity of the B-myb promoter.
Breast cancer (BC) is a common disease that generally occurs in women over the age of 50, and the risk is especially high for women over 60 years of age. One of the major BC therapeutic problems is that tumors initially responsive to chemotherapeutic approaches can progress to more aggressive forms poorly responsive to therapies. Polyamines (PAs) are small polycationic alkylamines, naturally occurring and essential for normal cell growth and development in eukaryotes. The intracellular concentration of PA is maintained within strongly controlled contents, while a dysregulation occurs in BC cells. Polyamines facilitate the interactions of transcription factors, such as estrogen receptors with their specific response element, and are involved in the proliferation of ER-negative and highly invasive BC tumor cells. Since PA metabolism has a critical role in cell death and proliferation, it represents a potential target for intervention in BC. The goal of this study was to perform a literature search reviewing the association between PA metabolism and BC, and the current evidence supporting the BC treatment targeting PA metabolism. We here describe in vitro and in vivo models, as well as the clinical trials that have been utilized to unveil the relationship between PA metabolism and BC. Polyamine pathway is still an important target for the development of BC chemotherapy via enzyme inhibitors. Furthermore, a recent promising strategy in breast anticancer therapy is to exploit the self-regulatory nature of PA metabolism using PA analogs to affect PA homeostasis. Nowadays, antineoplastic compounds targeting the PA pathway with novel mechanisms are of great interest and high social impact for BC chemotherapy.
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