| 1. |
- Brix, Ditte Marie, et al.
(författare)
-
Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion
- 2019
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:17, s. 3170-3184
-
Tidskriftsartikel (refereegranskat)abstract
- HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.
|
|
| 2. |
- Hansson, Oskar, et al.
(författare)
-
Overexpression of heat shock protein 70 in R6/2 Huntington's disease mice has only modest effects on disease progression.
- 2003
-
Ingår i: Brain Research. - 1872-6240. ; 970:1-2, s. 47-57
-
Tidskriftsartikel (refereegranskat)abstract
- Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a polyglutamine tract in a protein called huntingtin. The inducible form of heat shock protein 70 (Hsp70) has been shown to reduce polyglutamine-induced toxicity. To investigate if overexpression of Hsp70 can affect disease progression in a mouse model of HD, we crossed R6/2 mice, expressing exon 1 of the HD gene with an expanded CAG repeat, with mice overexpressing Hsp70 (both types of transgenic mice were of the CBAxC57BL/6 strain). The resulting R6/2-Hsp70 transgenics exhibited 5- to 15-fold increases in Hsp70 expression in neocortical, hippocampal and basal ganglia regions. This correlated with a delayed loss of body weight compared to R6/2 mice. However, the number or size of nuclear inclusions, the loss of brain weight, reduction of striatal volume, reduction in size of striatal projection neurons, downregulation of DARPP-32, development of paw clasping phenotype and early death of the mice were not affected by Hsp70 overexpression. Interestingly, the polyglutamine protein affected the potential rescuing agent, because in older R6/2-Hsp70 mice a large proportion of the Hsp70 protein was sequestrated in nuclear inclusions.
|
|
| 3. |
|
|
| 4. |
- Korhonen, Laura, 1974-
(författare)
-
Anti-Apoptotic Proteins in Nerve Cell Survival and Neurodegeneration
- 2002
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apoptosis is a genetically regulated cell death program, which shows distinct morphological characteristics. It takes place during neuronal development and in some neurodegenerative diseases. During apoptosis, the intracellular proteins are degraded by various caspases, cysteine aspartases, which are regulated by pro- and anti-apoptotic signals. This thesis elucidates the role of anti-apoptotic proteins in nerve cell survival and neurodegeneration. Studies have focused on Bcl-2 family members and Inhibitor of Apoptosis Proteins (IAP).XIAP and RIAP-2 are IAP proteins, which are expressed by neurons in the central nervous system. Kainic acid, a glutamate receptor agonist that induces seizures, increased XIAP immunoreactivity in rat hippocampus, whereas RIAP-2 expression in the same time decreased in degenerating neurons. Both XIAP and RIAP-2 were absent in dying neurons indicating that these proteins have a protective role in kainic acid induced neurodegeneration.NAIP, another IAP family member, was shown to interact with the calcium binding protein Hippocalcin using the yeast two-hybrid system and immunoprecipitation experiments. Hippocalcin-NAIP interaction increased motoneuron survival in caspase-3 independent and dependent manners.The anti-apoptotic Bcl-2 proteins, Bcl-2 and Bcl-x, were studied using cultured neurons and human neuronal progenitor cells. In the progenitor cells, Bcl-2 overexpression enhanced cell survival and induced downregulation of Caspase-2 (ICH-1) and caspase-3 (YAMA/CPP32). These results suggest a novel mechanism for the action of Bcl-2.Estrogen was shown to inhibit death of cultured dorsal root ganglion neurons (DRG) after nerve growth factor withdrawal. The hormone increased the levels of Bcl-x, which may explain the known neuroprotective function of estrogen.
|
|
| 5. |
- Kågedal, Katarina, 1970-
(författare)
-
Cathepsin D released from lysosomes mediates apoptosis
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Last year (2002), the Nobel Prize in Physiology or Medicine was awarded to three scientists who have conducted pioneer research on programmed cell death. In the human body, more than a thousand billion cells are created every day, and an equal number die, thus programmed cell death, or apoptosis, is an important mechanism for maintaining tissue homeostasis and protecting against disease. Malfunctioning apoptosis is associated with many pathological conditions, for example, excess apoptosis is characteristic of AIDS, stroke, neurodegenerative diseases, and myocardinal infarction, and insufficient apoptosis is seen in autoimmune conditions and cancer. Robert Horvitz, one of the mentioned Nobel Prize Laureates, was the first to identify death genes, namely ced-3, -4, and -9 in the nematode Caenorhabditis elegans, which were later discovered to have counterparts in humans.The aim of this thesis is to clarify the participation of lysosomes and lysosomal proteases in the initiation of apoptosis. The lysosomal enzyme cathepsin D regulates the human homologue of ced-3, which encoded the caspase family of proteases. Moreover, the human homologue of ced-9 encodes the Bcl-2 family of proteins such as Bax, which was involved in regulating the release of cathepsin D from lysosomes during apoptosis. In the present studies, apoptosis was induced by various substances, all of which first caused damage to lysosomes with ensuing release of lysosomal proteases. Fibroblasts exposed either to free radicals generated by the redox cycling quinone naphthazarin or to the kinase inhibitor staurosporine exhibited rapid translocation of cathepsin D from lysosomes to the cytosol and subsequent apoptosis. Malignant macrophages (J774 cells) and T lymphocytes (Jurkat cells) exposed to the lysosomotropic detergent sphingosine displayed early lysosomal destabilization and later apoptosis. Sphingosine also destabilized isolated lysosomes. Moreover, mimicking the translocation of cathepsin D by microinjecting cathepsin D into the cytosol induced apoptosis in fibroblasts.In the mentioned systems, lysosomes were destabilized before mitochondrial changes occurred and caspases were activated. Furthermore, apoptosis was prevented by inhibition of cathepsin D in the naphthazarin, staurosporine, and sphingosine systems and by inhibition of cysteine proteases such as cathepsins B and L in the sphingosine system. These results emphasize that cytosolic localization of lysosomal proteases is necessary for the ability of these enzymes to induce apoptosis.The present results also demonstrate that, during apoptosis, lysosomal membranes are destabilized by the following: (i) free-radical-mediated lipid peroxidation; (ii) pore formation through the Bcl-2 family member Bax; (iii) the impact of the lysosomotropic detergent sphingosine. All three of these events have been implicated in numerous other apoptosis systems. Accordingly, the participation of lysosomal enzymes in apoptosis may be more widespread than previously assumed. This new perspective on lysosomes as regulators of apoptosis may lead to novel treatment strategies for diseases associated with malfunctioning apoptosis.
|
|
| 6. |
- Olsson, Tomas, et al.
(författare)
-
Lack of neuroprotection by heat shock protein 70 overexpression in a mouse model of global cerebral ischemia.
- 2004
-
Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 154:4, s. 442-449
-
Tidskriftsartikel (refereegranskat)abstract
- Heat shock protein 70 (Hsp70) is induced in cells by a variety of stress conditions, is known to be cytoprotective, and has been proposed to be neuroprotective during brain ischemia. A recently developed mouse model of 12-min global cerebral ischemia by bilateral common carotid artery occlusion with artificial ventilation and bilateral monitoring of regional cerebral blood flow by laser Doppler was applied. We examined the expression and possible neuroprotective role of the inducible form of Hsp70 in the mouse brain following global cerebral ischemia. Ischemia induced a marked expression of Hsp70 in the ischemia vulnerable CA1-CA3 region of the hippocampus. Intraischemic hypothermia (33degreesC) prevented cell damage without noticeable expression of Hsp70. A transgenic mouse overexpressing Hsp70 was subjected to 12 min of global cerebral ischemia, and the brain damage was evaluated after 4 days. No neuroprotection of ischemia-induced brain damage in hippocampus, striatum, cortex or thalamus was found in Hsp70 transgenic animals compared with wild-type littermate mice. We suggest that overexpression of Hsp70 following cerebral ischemia is an indicator of cell stress. Also, constitutively overexpression of Hsp70 is insufficient to effectively influence cell death after global cerebral ischemia in the mouse.
|
|
