Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:[Age-dependent peculiarities of apoptotic marker proteins expression in the neuroendocrine system of Her2/neu transgenic mice]. 1772 67

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.
 ...
PMID:[Apoptosis regulation in hypothalamic neurosecretory cells of HER2/neu transgenic mice in ontogenesis]. 1838 7

Human epidermal growth factor receptor-2 (HER-2/ErbB2/neu), a receptor tyrosine kinase that is amplified/overexpressed in poor prognosis breast carcinomas, confers resistance to apoptosis by activating cell survival pathways. Here we demonstrate that the cytoplasmic tail of HER-2 is cleaved by caspases at Asp(1016)/Asp(1019) to release a approximately 47-kDa product, which is subsequently proteolyzed by caspases at Asp(1125) into an unstable 22-kDa fragment that is degraded by the proteasome and a predicted 25-kDa product. Both the 47- and 25-kDa products translocate to mitochondria, release cytochrome c by a Bcl-x(L)-suppressible mechanism, and induce caspase-dependent apoptosis. The 47- and 25-kDa HER-2 cleavage products share a functional BH3-like domain, which is required for cytochrome c release in cells and isolated mitochondria and for apoptosis induction. Caspase-cleaved HER-2 binds Bcl-x(L) and acts synergistically with truncated Bid to induce apoptosis, mimicking the actions of the BH3-only protein Bad. Moreover, the HER-2 cleavage products cooperate with Noxa to induce apoptosis in cells expressing both Bcl-x(L) and Mcl-1, confirming their Bad-like function. Collectively, our results indicate that caspases activate a previously unrecognized proapoptotic function of HER-2 by releasing a Bad-like cell death effector.
 ...
PMID:Caspase cleavage of HER-2 releases a Bad-like cell death effector. 1842 May 86

Phenethyl isothiocyanate (PEITC) is a highly promising cancer chemopreventive constituent of cruciferous vegetables (e.g., watercress) with in vivo efficacy in experimental rodent cancer models. Research thus far implicates apoptosis induction in cancer chemopreventive response to PEITC, but the mechanism of proapoptotic effect is not fully understood. The present study demonstrates that p53 upregulated modulator of apoptosis (PUMA)-independent apoptosis by PEITC is mediated by B-cell lymphoma 2 interacting mediator of cell death (Bim). Exposure of a cell line (BRI-JM04) derived from spontaneously developing mammary tumor of a MMTV-neu transgenic mouse to pharmacological concentrations of PEITC resulted in decreased cell viability coupled with apoptosis induction, characterized by release of histone-associated DNA fragments into the cytosol and cleavage of poly-(ADP-ribose)-polymerase and procaspase-3. The PEITC-induced apoptosis in BRI-JM04 cells was associated with up-regulation of Bak, PUMA, and Bim (long and short forms of Bim), increased S65 phosphorylation of BimEL (extra-long form), and down-regulation of Bcl-xL and Bcl-2. On the other hand, a non-tumorigenic human mammary epithelial cell line (MCF-10A) was significantly more resistant to PEITC-induced apoptosis compared with BRI-JM04 despite induction of Bax and PUMA due to concomitant overexpression of anti-apoptotic proteins, including Bcl-xL, Bcl-2, and Mcl-1. Wild-type HCT-116 cells and its isogenic PUMA knockout variant exhibited comparable sensitivity to PEITC-induced apoptosis. On the other hand, small interfering RNA knockdown of Bim protein imparted partial but statistically significant protection against PEITC-induced apoptosis in BRI-JM04, MCF-7, and MDA-MB-231 cells. In conclusion, the present study provides novel insight into the mechanism of PEITC-induced apoptosis involving Bim.
 ...
PMID:Bim contributes to phenethyl isothiocyanate-induced apoptosis in breast cancer cells. 2173 79

Neurodegenerative changes and neuronal death are the basis for development of the nervous system aging. We investigated the mechanism of apoptosis of the sensorimotor cortex neurons of transgenic mice HER2/neu during aging, changes in the cortex function and the participation of exogenous neurometabolites (cytoflavin, piracetam) in regulation of neuronal death and locomotor and psycho-emotional status of mice. The level of apoptosis and expression of apoptosis markers (TUNEL, immunohistochemistry, Western blotting) in HER2/neu transgenic mice as compared to wild type mice (FBV line) were determined. In aging FBV mice the basal activity was shown to decrease and anxiety to increase correlating with the high level of neuronal apoptosis. We identified behavioral characteristics of transgenic HER2/neu mice and found that their low basal activity does not change with aging. Previously we have shown that in this strain of mice the apoptosis level is low, without any age-related changes, due to the suppression, first of all, of the p53-dependent pathway by HER2 (tyrosine kinase receptor) overexpression. Cytoflavin and piracetam were revealed to possess a marked neuroprotective effect, preserving and restoring functions of the nervous system (improving locomotion and psychological status) in both strains of mice. The effect of neurometabolites studied on neuronal apoptosis is ambiguous. In case of its low level it is a moderate stumulation of apoptosis via the external p53-dependent pathways with activation of caspase-3 in transgenic HER2/neu mice with high carcinogenesis level that can possibly prevent tumor development. On the contrary, in old wild-type animals we observed a significant decrease of age-dependent apoptosis level (by stimulating expression of the anti-apoptotic protein Mcl-1), which prevents neurodegeneration.
 ...
PMID:[PHARMACOLOGICAL CORRECTION OF APOPTOSIS LEVEL OF CORTICAL NEURONS IN AGED HER2/NEU TRANSGENIC MICE]. 2722 Feb 41