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ScienceWeek
NEUROSCIENCE: ON SMALL HEAT SHOCK PROTEINS
The following points are made by M.D. Perng and R.A. Quinlan (Current Biology 2004 14:R625):
1) Members of the small heat shock protein (sHSP) family are protein chaperones [1] that are important in the stress response of cells, particularly neurons [2]. These chaperones protect against a variety of stresses, from heat to oxidative stress and usually have anti-apoptotic activity [2,3]. One of the family members, HSPB1, can also suppress the toxic effects of the polyglutamine protein, huntingtin, and decrease the levels of reactive oxygen species produced as part of the response to this toxic protein [3]. Coincidentally, sHSPs are often upregulated in neurodegenerative diseases [4] and also in motor neurone cell injury [2]. The protective activity of these proteins can be cell-type dependent because HSPB1 protects against apoptotic stimuli in neurons [2,3], but not cardiomyocytes [5]. Some sHSPs, like HSPB8 are even pro-apoptotic, despite being upregulated in disease. Recent studies have identified a genetic link between HSPB1 and HSPB8 and the distal neuropathies, Charcot Marie Tooth Disease (CMT) and Hereditary Distal Motor Neuropathy (HMN), exposing an important gap in our knowledge, namely the function of these specific sHSPs in motor neurons.
2) The sHSPs form a large protein family [1] comprising proteins typified by a highly conserved sequence of 90 amino acid residues in the carboxy-terminal region, called the alpha-crystallin domain, and by their relatively low molecular weight (20-25 kDa). Of the 10 different human sHSPs that are currently known [1], some, like HSPB1, are widely expressed, whereas others, such as HSPB8, are more restricted in their expression. Both HSPB1 and HSPB8 are found in the nervous system, where they are expressed in different neuronal cell types, although both are expressed in motor neurons. HSPB8, on the other hand, is highly expressed in heart and liver with reduced levels in skeletal muscle, lung, kidney, testis and brain. These observations of the sHSP expression patterns pose the question: why are motor neurons the specific target of the HSPB1 and HSPB8 mutations?
3) At least part of the answer lies in the diversity of the interactions and functions of sHSPs, which explains why there is not necessarily a direct correlation between sHSP levels and the tissue affected by the sHSP mutations. HSPB1 and HSPB8 operate in association with other sHSPs, as well as with other chaperones, such as those of the HSP70 class. HSPB8 also has kinase activity and potentially has a direct link to the Akt/PKB kinase pathway. This complexity makes identifying a unique function for these proteins quite a difficult task, especially when one considers that potential targets can include individual proteins as well as macromolecular structures such as the cytoskeleton.
References (abridged):
1. Kappe, G., Franck, E., Verschuure, P., Boelens, W.C., Leunissen, J.A. and de Jong, W.W. (2003). The human genome encodes 10 alpha-crystallin-related small heat shock proteins: HspB1-10. Cell Stress Chaperones 8, 53-61
2. Benn, S.C., Perrelet, D., Kato, A.C., Scholz, J., Decosterd, I., Bakowska, J.C. and Woolf, C. (2002). HSP27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron 36, 45-56
3. Wyttenbach, A., Sauvageot, O., Carmichael, J., Diaz-Latoud, C., Arrigo, A.P. and Rubinsztein, D.C. (2002). Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum. Mol. Genet. 11, 1137-1151
4. Dabir, D.V., Trojanowski, J.Q., Richter-Landsberg, C., Lee, V.M. and Forman, M.S. (2004). Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. Am. J. Pathol 164, 155-166
5. Kamradt, M.C., Chen, F., Sam, S. and Cryns, V.L. (2002). The small heat shock protein alpha B-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation. J. Biol. Chem. 277, 38731-38736
Current Biology http://www.current-biology.com
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CANCER BIOLOGY: ON HEAT SHOCK PROTEINS AND TUMOR CELLS
The following points are made by L. Neckers and Y-S. Lee (Nature 2003 425:357):
1) Targeting a specific protein or a single signalling pathway that is required for the survival of tumour cells but not normal cells would seem to be a promising anticancer strategy. Unfortunately, few such unique targets exist, and it is becoming clear that inhibiting a single pathway might not be enough to tackle cancers that result from several genetic abnormalities. Instead, attention is turning to proteins such as heat-shock protein 90 (Hsp90) that regulate many signalling pathways in cancer cells.
2) In 1962, while looking at the salivary-gland chromosomes of the fruitfly Drosophila, Ferruccio Ritossa noticed that certain regions of the chromosomes puffed out in response to a sudden increase in temperature(3). The gene products encoded on these chromosome puffs were later isolated and termed "heat-shock proteins", or Hsps. The production of Hsps accelerates in response to temperature stress, but these proteins are abundant even in unstressed cells. Hsps have been more accurately called "molecular chaperones", because they protect other cellular proteins from becoming misshapen as a result of high temperature or other environmental insults, and certain Hsps also enable newly synthesized proteins to attain the correct conformation.
3) One particular chaperone, Hsp90, has been implicated in the survival of cancer cells(4). Hsp90 regulates the function and stability of many key signalling proteins that help cancer cells to escape the inherent toxicity of their environment, to evade the effects of chemotherapy, and to protect themselves from the results of their own genetic instability. So inhibitors of Hsp90 could mount a multi-pronged assault on cancer cells that, if not lethal itself, might leave them sufficiently debilitated to allow control by chemotherapy or radiotherapy.
4) One feature of Hsp90 has concerned investigators -- although cancer cells can produce high levels of the protein(1), it is also abundant in normal cells. This might mean that drugs targeting Hsp90 prove to be unacceptably toxic. Surprisingly, however, the first Hsp90 inhibitor to be tested in clinical trials, the drug 17-AAG, has been well tolerated by patients. Kamal et al(2) have provided data that begin to explain this apparent paradox. These authors have reported that Hsp90 found in tumour cells has a much higher affinity for 17-AAG than does Hsp90 from normal cells.(5)
References (abridged):
1. Ferrarini, M., Heltai, S., Zocchi, M. R. & Rugarli, C. Int. J. Cancer 51, 613-619 (1992)
2. Kamal, A. et al. Nature 425, 407-410 (2003)
3. Ritossa, F. Cell Stress Chaperones 1, 97-98 (1996)
4. Maloney, A. & Workman, P. Expert Opin. Biol. Ther. 2, 3-24 (2002)
5. Chiosis, G. et al. Chem. Biol. 8, 289-299 (2001)
Nature http://www.nature.com/nature
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ON HEAT SHOCK PROTEINS
In a multicellular organism, the differentiation of structure and function among various types of cells depends on which genes in the genome are activated. Every cell in an organism carries the same genome, but the set of operating genes differs from cell type to cell type. One central question, therefore, is how are genes selected for activation? In bacteria, groups of related genes are organized into "operons" whose *transcription is regulated by repressor and/or regulator proteins that bind to specific DNA sequences.
But operons have not been found in *eukaryotes. However, DNA sequences that play a role in regulating the transcription of genes in response to specific signals have been identified near the *transcriptional start sites of various eukaryotic genes. Because these sequences allow transcription to be regulated in response to a particular type of signal, they are referred to as "response elements". Placement of the same response element next to genes residing at different locations allows the transcription of such a group of genes to be regulated by the same signal even though the genes are not adjacent to each other.
One of the first DNA response elements to be identified is a nucleotide sequence that coordinates the activity of genes whose products protect organisms against excessive heat. If cells growing in culture are briefly warmed by raising the temperature a few degrees, the transcription of several "heat-shock" genes is activated. It has been found that if a heat-shock response element can be identified, relocation of that response element (by genetic engineering) to a gene which is not normally a heat-shock gene will turn that gene into a heat-shock gene.
Experiments have revealed that the activation of heat-shock genes is mediated by the binding of a protein called the "heat-shock transcription factor" to the heat-shock response element. The heat-shock transcription factor is apparently present in an inactive form in non-heated cells, but elevation of temperature causes a change in the structure of the protein, and this change allows the protein to bind to the heat-shock response element in DNA.
What is most important about the regulation of heat-shock genes is that the basics of this regulation are apparently involved in the regulation of other eukaryotic genes, and as a result the molecular biology of heat-shock proteins has become a paradigm useful for the understanding of eukaryotic gene regulation.
The following points are made by Richard I. Morimoto (Genes & Development 15 Dec 98 12:3788):
1) In stressed environments, proteins can unfold, misfold, or aggregate. The heat-shock response, through the elevated synthesis of *molecular chaperones and *proteases, repairs protein damage and assists in the recovery of the cell.
2) The induction of transcription of heat shock genes is a response to a number of stress signals, including environmental stresses, certain non-stress conditions, and various disease states. Although changes in heat-shock protein expression have been associated with certain diseases, it is not clear whether the changes are an adaptation to the particular disease state, a reflection of the suboptimal cellular environment associated with the disease state, or a signal warning other cells and tissues of imminent danger.
3) The protective role of heat-shock proteins is a measure of their capacity to assist in the repair of protein damage. Whether in *prokaryotes, plants, or animals, overexpression of one or more heat-shock proteins is often sufficient to protect cells and tissues against otherwise lethal exposure to diverse environmental stresses (e.g., hydrogen peroxide and other oxidants, toxic chemicals, extreme temperatures, ethanol-induced toxicity). In vertebrate tissue culture cells and animal models, elevating the population of heat-shock proteins by various methods restricts or substantially reduces the level of pathology and cell death following environmental stress. This has led to the recognition that heat-shock proteins, via their chaperoning effects on other proteins, protect cells from many forms of stress-induced cell damage and can influence the course of disease states.
4) Future studies will establish how different members of the heat-shock transcription factor gene family either respond to different forms of stress, ensure regulation of distinct stages of activation or repression of the heat-shock response, or provide an interface between the stress response and other transcription regulatory pathways.
Genes & Development http://www.genesdev.org
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Notes by ScienceWeek:
transcription: Transcription is the process by which the genetic information in DNA is converted into RNA, and transcription factors are a class of DNA-binding proteins that regulate RNA transcription. Transcription factor genes are simply the genes that code for the transcription factor proteins.
eukaryotes: Cells (and organisms consisting of such cells) that contain intracellular membrane-bound compartments such as a nucleus (membrane-bound "organelles"). Prokaryotes are unicellular or filamentous organisms in which cells lack internal membrane compartments such as a nucleus. E.g., bacteria.
transcriptional start sites: (transcription start points) In this context, a start site or start point is the base pair in DNA at which the first nucleotide is incorporated into an RNA transcript. It is most often a purine, and in many cases is the central base in the sequence cytosine-adenine-thymine. The term "start site" should not be confused with "start codon", which is the trinucleotide adenine-uracil-guanine that codes for the first amino acid residue in the synthesis of all prokaryotic and mitochondrial proteins.
mitochondrial proteins: Mitochondria are organelles of the cell cytoplasm, and the principal energy source of the cell. They contain various enzymes involved in electron transport and metabolic cycles.
molecular chaperones: In general, chaperone proteins are proteins required for the proper folding and/or assembly of another protein or protein complex.
proteases: A protease is an enzyme that splits proteins and thereby degrades them.
ScienceWeek http://scienceweek.com
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