ABSTRACT
The aim of the present work was to identify the characteristics of the control of apoptosis in neurosecretory centers of aged (18 months) mice on exposure to the immunomodulator interferon-alpha (IA) in comparison with young (two months) mice. Age-related activation of apoptosis in the supraoptic (SON) and paraventricular (PVN) nuclei was found to be mediated by different pathways and could result from changes in the ratio of synthesis of pro-(Bax) and antiapoptotic (Mcl-1, Bcl-2) molecules. In addition, the apoptosis signal cascade in young mice treated with IA was identical in both nuclei, while in aged mice there were differences between the SON and the PVN.
Subject(s)
Aging/metabolism , Apoptosis Regulatory Proteins/metabolism , Apoptosis/physiology , Neurosecretory Systems/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Supraoptic Nucleus/metabolism , Animals , Immunohistochemistry , Interferon-alpha/physiology , Male , Mice , Myeloid Cell Leukemia Sequence 1 Protein , Neoplasm Proteins/metabolism , Neurosecretory Systems/cytology , Paraventricular Hypothalamic Nucleus/cytology , Proto-Oncogene Proteins c-bcl-2/metabolism , Statistics, Nonparametric , Supraoptic Nucleus/cytology , bcl-2-Associated X Protein/metabolismABSTRACT
The aim of our work was to study the expression of apoptotic signaling proteins and its relation to apoptosis level in neuroendocrine system of HER2/neu transgenic mice in aging. SHR mice served as controls. Bcl-2, Mcl-1, p53 and caspase-8 were demonstrated by immunohistochemistry in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and relative content of apoptotic neurosecretory cells was determined. It was demonstrated that apoptosis regulation in different nuclei in old SHR mice was mediated by various signaling pathways: in SON, p53-independent cascade was activated, while in PVN it was p53-dependent. Overexpression of HER2/neu was shown to protect against the age-related apoptosis activation in neurosecretory centers. HER2/neu suppressed the synthesis of proapoptotic protein p53, causing the reduction of caspase-8 expression, that resulted in the increased survival of neurosecretory cells in aging.
Subject(s)
Aging/genetics , Apoptosis , Caspase 8/biosynthesis , Neoplasm Proteins/biosynthesis , Neurosecretory Systems , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Receptor, ErbB-2/genetics , Tumor Suppressor Protein p53/biosynthesis , Animals , Apoptosis/genetics , Apoptosis/physiology , Genes, erbB-2 , Male , Mice , Mice, Transgenic , Myeloid Cell Leukemia Sequence 1 Protein , Neurosecretory Systems/metabolism , Neurosecretory Systems/physiology , Paraventricular Hypothalamic Nucleus/metabolism , Paraventricular Hypothalamic Nucleus/physiology , Receptor, ErbB-2/biosynthesis , Supraoptic Nucleus/metabolism , Supraoptic Nucleus/physiology , TransgenesABSTRACT
Tyrosine kinase receptor HER2/neu plays an important role in a number of processes including carcinogenesis. The oncogenic characteristics of HER2/neu are associated with its ability to affect a variety of apoptotic pathways creating, this way, an antiapoptotic environment in the cells overexpressing this protein. The aim of our work was to investigate the features of apoptosis regulation in hypothalamic neurosecretory cells of HER2/neu transgenic mice in aging. We detected the apoptosis protein expression (Bax, c-Raf) in comparison with apoptosis level and functional activity (vasopressin concentration) in neuroendocrine system. Besides, we studied the level of 17beta-estradiol in blood plasma. 17beta-estradiol is one of possible antiapoptotic factors in neurons. We show that the apoptosis of neuroendocrine cells increases in aged wild type mice, but not in HER2/neu ones. Recently we obtained that the mechanism of apoptosis suppression in transgenic mice is the block of p53-dependent apoptosis cascade, and it is the cause of caspadse-8 decrease and dysregulation of Bcl-2 and Mcl-1 antiapoptotic protein synthesis. In this study it has been shown that Bax concentration decreases and c-Raf-1 expression does not change. 17beta-estradiol does not decrease in plasma of aged transgenic mice and it is the factor, which can play a positive role in neuroendocrine cells survival. Besides, the vasopressin synthesis increases in young and old HER2 mice. These facts result in the increased survival of neurosecretory cells in old transgenic mice.
Subject(s)
Aging , Apoptosis , Hypothalamus/pathology , Neurosecretory Systems/pathology , Receptor, ErbB-2/genetics , Aging/genetics , Aging/pathology , Animals , Apoptosis/genetics , Estradiol/blood , Hypothalamus/metabolism , Immunohistochemistry , Male , Mice , Mice, Transgenic , Neurosecretory Systems/metabolism , Proto-Oncogene Proteins c-raf/biosynthesis , Vasopressins/blood , bcl-2-Associated X Protein/biosynthesisABSTRACT
The aim of work was to study the peculiarities of apoptosis regulation in neurosecretory centers of old (aged 18 months) mice treated with immunomodulator interferon alpha (IFN-alpha) as compared to young (aged 2 months) mice. It was shown that age-related apoptosis activation in supraoptic (SON) and paraventricular (PVN) nuclei was mediated by different molecular mechanisms and could result from the alterations of the balance of apoptosis-associated proteins, including the synthesis of proapoptotic (Bax) and antiapoptotic (Mcl-1, Bcl-2) molecules. Besides, the apoptosis signal cascade in young mice treated with IFN-alpha was identical in both nuclei, whereas in old mice there were some differences between SON and PVN.
