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1.
Wikenheiser-Brokamp KA 《Cellular and molecular life sciences : CMLS》2006,63(7-8):767-780
The retinoblastoma (Rb) gene was identified as the first tumor suppressor gene two decades ago. Since this initial discovery,
it has become clear that deregulated Rb function constitutes a hallmark of human malignancies. Rb is a well-established regulator
of the cell cycle. Rb has also been implicated in playing a role in a wide variety of cellular processes including DNA repair,
cellular senescence, cell fate determination and apoptosis. Animals lacking Rb and/or its family members p107 and p130 have
led scientists to uncover new and exciting roles for this protein family in development as well as tumor suppression. The
ability to ablate Rb in a temporal and cell-type-specific manner has offered further, often unexpected, insights into Rb function.
This review summarizes the phenotypic consequences of Rb family ablation in mice, and discusses how these findings contribute
to the increasingly complex picture of Rb family function in development and tumor suppression.
Received 11 October 2005; received after revision 16 November 2005; accepted 28 November 2005 相似文献
2.
Morrison BE Majdzadeh N D'Mello SR 《Cellular and molecular life sciences : CMLS》2007,64(17):2258-2269
Neurodegenerative disease strikes millions worldwide and there is mounting evidence suggesting that underlying the onset and
progression of these debilitating diseases is inappropriate neuronal apoptosis. Recent reports have implicated a family of
proteins known as histone deacetylases (HDACs) in various neuronal processes including the neuronal death program. Initial
headway in this field has been made largely through the use of broad-spectrum HDAC inhibitors. In fact, pharmacological inhibition
of HDAC activity has been shown to protect neurons in several models of neurodegeneration. The observation that HDAC inhibitors
can have opposing effects in different paradigms of neurodegeneration suggests that individual members of the HDAC protein
family may play distinct roles that could depend on the specific cell type under study. The purpose of this review is to detail
work involving the use of HDAC inhibitors within the context of neurodegeneration and examine the roles of individual HDAC
members in the nervous system with specific focus on neuronal cell death.
Received 25 January 2007; received after revision 3 April 2007; accepted 26 April 2007 相似文献
3.
The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis,
senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression.
ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with
histone trimethylated at lysine 4 (H3K4me3), hypoxia inducible factor-1 (HIF-1), p53, and nuclear factor kappa-B (NF-κB) are
potential mechanisms by which ING members exert effects on invasion and metastasis. Subcellular mislocalization, rapid protein
degradation, and to a lesser extent ING gene mutation are among the mechanisms responsible for inappropriate ING levels in cancer cells. The aim of this review is
to summarize the different roles of ING family tumor suppressors in cancer progression and the molecular mechanisms involved. 相似文献
4.
Retinal proteins function as photoreceptors and ion pumps. Xanthorhodopsin of Salinibacter ruber is a recent addition to this diverse family. Its novel and distinctive feature is a second chromophore, a carotenoid, which
serves as light-harvesting antenna. Here we discuss the properties of this carotenoid/retinal complex most relevant to its
function (such as the specific binding site controlled by the retinal) and its relationship to other retinal proteins (bacteriorhodopsin,
archaerhodopsin, proteorhodopsin and retinal photoreceptors of archaea and eukaryotes). Antenna addition to a retinal protein
has not been observed among the archaea and emerged in bacteria apparently in response to environmental conditions where light-harvesting
becomes a limiting factor in retinal protein functioning.
Received 2 April 2007; received after revision 14 May 2007; accepted 16 May 2007 相似文献
5.
Levy-Favatier F Leroux A Antoine B Nedelec B Delpech M 《Cellular and molecular life sciences : CMLS》2004,61(22):2886-2892
In a previous study, we identified and purified a 99-amino-acid rat liver-kidney perchloric-acid-soluble 23-kDa protein (P23) which displays 30% identity with a highly conserved domain of heat shock proteins (HSPs), as well as an AT-rich 3 untranslated region, which has also been described to play a role in H70 mRNA life span and protein expression. An identical perchloric-acid-soluble protein inhibiting protein synthesis in a rabbit reticulocyte lysate system was also found 2 years later by another group. More recently, the novel, the YjgF, protein family has been described, comprising, 24 full-length homologues, including P23, highly conserved through evolution, and consisting of approximately 130 residues each and sharing a common ternary structure. Independent studies from different laboratories have provided various hypothetical functions for each of these proteins. The high degree of evolutionary conservation may suggest that these proteins play an important role in cellular regulation. Although the function of none of these proteins is known precisely, we present experimental evidence which, combined with the relationship to glucose-regulating protein revealed here, and the relationship to fatty-acid-binding protein revealed by others, allow us to propose a role for P23. In rat liver, P23 expression is developmentally regulated and modulated by dietary glucose, and its mRNA is induced by starvation, in the presence of fatty-acids and in 3-MeDAB-induced hepatomas. The mRNA encoding mouse liver P23 is also hormonally modulated in a mouse line AT1F8. These data indicate that P23 protein might be a key controller of intermediary metabolism during fasting.Received 7 June 2003; received after revision 8 September 2004; accepted 10 October 2004 相似文献
6.
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified as a key regulator of insulin-dependent
glycogen synthesis. GSK-3 was subsequently shown to function in a wide range of cellular processes including differentiation,
growth, motility and apoptosis. Aberrant regulation of GSK-3 has been implicated in a range of human pathologies including
Alzheimer’s disease, non-insulin-dependent diabetes mellitus (NIDDM) and cancer. As a consequence, the regulation of GSK-3
and the therapeutic potential of GSK-3 inhibitors have become key areas of investigation. This review will focus on the mechanisms
of GSK-3 regulation, with emphasis on modulation by upstream signals, control of substrate specificity and GSK-3 localisation.
The details of these mechanisms will be discussed in the context of specific signalling pathways.
Received 30 January 2007; received after revision 5 March 2007; accepted 16 April 2007 相似文献
7.
Studies in the past years have implicated multispan transmembrane transport molecules of the ATP binding cassette (ABC) transporter
family in cellular lipid export processes. The prototypic ABC transporter ABCA1 has recently been demonstrated to act as a
major facilitator of cellular cholesterol and phospholipid export. Moreover, the transporter ABCA4 (ABCR) plays a pivotal
role in retinaldehyde processing, and ABCA3 has recently implicated in lung surfactant processing. These pioneering observations
have directed considerable attention to the A subfamily of ABC proteins. ABCA2 is the codefining member of the ABC A-transporter
subclass. Although known for some time, it was not until recently that its complete molecular structure was established. Unlike
other ABC A-subfamily members, ABCA2 is predominantly expressed in the brain and neural tissues. The unique expression profile
together with available structural data suggest roles for this largest known ABC protein in neural transmembrane lipid export.
Received 31 January 2002; received after revision 11 March 2002; accepted 11 March 2002 相似文献
8.
C. Akgul 《Cellular and molecular life sciences : CMLS》2009,66(8):1326-1336
Resistance to apoptosis is a common challenge in human malignancies contributing to both progress of cancer and resistance
to conventional therapeutics. Abnormalities in a variety of cell intrinsic and extrinsic molecular mechanisms cooperatively
promote tumor formation. Therapeutic approaches that specifically target components of these molecular mechanisms are getting
widespread attention. Mcl-1 is a highly expressed pro-survival protein in human malignancies and its cellular expression is
tightly regulated via multiple mechanisms. Mcl-1 differs from other members of the Bcl-2 family in having a very short half-life. So inhibition
of its expression and/or neutralization of its anti-apoptotic function will rapidly make Mcl-1-dependent cells more susceptible
to apoptosis and provide an opportunity to combat several types of cancers. This review summarizes the current knowledge on
the regulation of Mcl-1 expression and discusses the alternative approaches targeting Mcl-1 in human cancer cells whose survivals
mainly depend on Mcl-1.
Received 6 October 2008; received after revision 21 October 2008; accepted 10 November 2008 相似文献
9.
Charcot-Marie-Tooth (CMT) disease serves as the summary term for the most frequent forms of inherited peripheral neuropathies that affect motor and sensory nerves. In the last 12 years, 14 genes have been identified that cause different CMT subforms. The genes found initially are predominantly responsible for demyelinating and dysmyelinating neuropathies. Genes affected in axonal and rare forms of CMT have only recently been identified. In this review, we will focus on the currently known genes that are associated with CMT syndromes with regards to their genetics and function.Received 5 April 2003; received after revision 20 May 2003; accepted 23 May 2003 相似文献
10.
Royet J 《Cellular and molecular life sciences : CMLS》2004,61(5):537-546
Over the past years, parallel studies conducted in mammals and flies have emphasized the existence of common mechanisms regulating the vertebrate and invertebrate innate immune systems. This culminated in the discovery of the central role of the Toll pathway in Drosophila immunity and in the implication of Toll-like receptors (TLRs)/interleukin-1(IL-1) in the mammalian innate immune response. In spite of clear similarities, such as shared intracellular pathway components, important divergences are expected between the two groups, whose last common ancestor lived more than half a billion years ago. The most obvious discrepancies lie in the mode of activation of the signalling receptors by microorganisms. In mammals, TLRs are part of protein complexes which directly recognize microbe-associated patterns, whereas Drosophila Toll functions like a classical cytokine receptor rather than a pattern recognition receptor. Recent studies demonstrate that members of the evolutionarily conserved peptidoglycan recognition protein family play an essential role in microbial sensing during immune response of Drosophila.Received 26 June 2003; received after revision 29 July 2003; accepted 25 August 2003 相似文献
11.
OSBP (oxysterol-binding protein) and ORPs (OSBP-related proteins) constitute an enigmatic eukaryotic protein family that is
united by a signature domain that binds oxysterols, sterols, and possibly other hydrophobic ligands. The human genome contains
12 OSBP/ORP family members genes, while that of the budding yeast Saccharomyces cerevisiae encodes seven OSBP homologues (Osh). Of these, Osh4 (also referred to as Kes1) has been the most widely studied to date.
Recently, three-dimensional crystal structures of Osh4 with and without sterols bound within the core of the protein were
determined. The core consists of 19 anti-parallel β-sheets that form a near-complete β-barrel. Recent work has suggested that
Osh proteins facilitate the non-vesicular transport of sterols in vivo and in vitro, while other evidence supports a role for Osh proteins in the regulation of vesicular transport and lipid metabolism.This
article will review recent advances in the study of ORP/Osh proteins and will discuss future research issues regarding the
ORP/Osh family.
Received 17 July 2007; received after revision 14 August 2007; accepted 12 September 2007 相似文献
12.
Reichert N Choukrallah MA Matthias P 《Cellular and molecular life sciences : CMLS》2012,69(13):2173-2187
Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the future. 相似文献
13.
Orsomando G Lorenzi M Ferrari E de Chiara C Spisni A Ruggieri S 《Cellular and molecular life sciences : CMLS》2003,60(7):1470-1476
The phytotoxic protein PcF (Phytophthora
cactorum-Fragaria) is a 5.6-kDa cysteine-rich, hydroxyproline-
containing protein that is secreted in limited amounts by P. cactorum, an oomycete pathogen of
tomato, strawberry and other relevant crop plants. Although we have shown that pure PcF triggers
plant reactivity, its mechanism of action is not yet understood. Here we show that PcF, like other
known fungal protein elicitors involved in pathogen-plant interaction, stimulates the activity of
the defense enzyme phenylalanine ammonia a key step in understanding the mechanism of action of
PcF at a molecular level is knowledge of its three-dimensional structure, we overexpressed this
protein extracellularly in Pichia pastoris. The preliminary
structural and functional characterization of a recombinant PcF homologue, N4-rPcF, is reported.
Interestingly, although N4-rPcF is devoid of proline hydroxylation and has four additional
amino acid residues attached to its N terminus, its secondary structure and biological activity are
indistinguishable from wild-type PcF.Received 22 February 2003; received after revision 25 March 2003; accepted 14 April 2003 相似文献
14.
Mitochondria are dynamic organelles and can undergo regulated fission/fragmentation to produce smaller organelles or, alternatively,
can undergo fusion to produce tubular or net-like mitochondrial structures. Although some of the molecules that control mitochondrial
fission and fusion are known, new molecules and pathways that control this process continue to be discovered, suggesting that
this process is more complex than previously appreciated. In addition to their crucial role in the regulation of apoptosis,
recent studies have implicated members of the Bcl-2 family in maintenance of the mitochondrial network. Here, we discuss the
mechanisms governing mitochondrial fission/fusion and summarize current knowledge concerning the role of Bcl-2 family members
in regulating mitochondrial fission/fusion dynamics. 相似文献
15.
Carboxypeptidases from A to Z: implications in embryonic development and Wnt binding 总被引:4,自引:0,他引:4
Carboxypeptidases perform many diverse functions in the body. The well-studied pancreatic enzymes (carboxypeptidases A1, A2 and B) are involved in the digestion of food, whereas a related enzyme (mast-cell carboxypeptidase A) functions in the degradation of other proteins. Several members of the metallocarboxypeptidase gene family (carboxypeptidases D, E, M and N) are more selective enzymes and are thought to play a role in the processing of intercellular peptide messengers. Three other members of the metallocarboxypeptidase gene family do not appear to encode active enzymes; these members have been designated CPX-1, CPX-2 and AEBP1/ACLP. In this review, we focus on the recently discovered carboxypeptidase Z (CPZ). This enzyme removes C-terminal Arg residues from synthetic substrates, as do many of the other members of the gene family. However, CPZ differs from the other enzymes in that CPZ is enriched in the extracellular matrix and is broadly distributed during early embryogenesis. In addition to containing a metallocarboxypeptidase domain, CPZ also contains a Cys-rich domain that has homology to Wnt-binding proteins; Wnts are important signaling molecules during development. Although the exact function of CPZ is not yet known, it is likely that this protein plays a role in development by one of several possible mechanisms. 相似文献
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18.
Huber O 《Cellular and molecular life sciences : CMLS》2003,60(9):1872-1890
Desmosomes represent major intercellular adhesive junctions at basolateral membranes of epithelial cells and in other tissues. They mediate direct cell-cell contacts and provide anchorage sites for intermediate filaments important for the maintenance of tissue architecture. There is increasing evidence now that desmosomes in addition to a simple structural function have new roles in tissue morphogenesis and differentiation. Transmembrane glycoproteins of the cadherin superfamily of Ca2+-dependent cell-cell adhesion molecules which mediate direct intercellular interactions in desmosomes appear to be of central importance in this respect. The complex network of proteins forming the desmosomal plaque associated with the cytoplasmic domain of the desmosomal cadherins, however, is also involved in junction assembly and regulation of adhesive strength. This re-view summarizes the structural features of these desmosomal proteins, their function during desmosome assembly and maintenance, and their role in development and disease.Received 5 February 2003; received after revision 14 March 2003; accepted 1 April 2003 相似文献
19.
Williams AE 《Cellular and molecular life sciences : CMLS》2008,65(4):545-562
MicroRNAs (miRNAs) are a recently discovered family of small regulatory molecules that function by modulating protein production.
There are approximately 500 known mammalian miRNA genes, and each miRNA may regulate hundreds of different protein-coding
genes. Mature miRNAs bind to target mRNAs in a protein complex known as the miRNA-induced silencing complex (miRISC), sometimes
referred to as the miRNP (miRNA-containing ribonucleoprotein particles), where mRNA translation is inhibited or mRNA is degraded.
These actions of miRNAs have been shown to regulate several developmental and physiological processes including stem cell
differentiation, haematopoiesis, cardiac and skeletal muscle development, neurogenesis, insulin secretion, cholesterol metabolism
and the immune response. Furthermore, aberrant expression has been implicated in a number of diseases including cancer and
heart disease. The role of miRNAs in these developmental, physiological and pathological processes will be reviewed.
Received 3 August 2007; received after revision 3 October 2007; accepted 5 October 2007 相似文献
20.
DnaJ/Hsp40 (heat shock protein 40) proteins have been preserved throughout evolution and are important for protein translation,
folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of chaperone proteins, Hsp70s.
Because the ATP hydrolysis is essential for the activity of Hsp70s, DnaJ/Hsp40 proteins actually determine the activity of
Hsp70s by stabilizing their interaction with substrate proteins. DnaJ/Hsp40 proteins all contain the J domain through which
they bind to Hsp70s and can be categorized into three groups, depending on the presence of other domains. Six DnaJ homologs
have been identified in Escherichia coli and 22 in Saccharomyces cerevisiae. Genome-wide analysis has revealed 41 DnaJ/Hsp40 family members (or putative members) in humans. While 34 contain the typical
J domains, 7 bear partially conserved J-like domains, but are still suggested to function as DnaJ/ Hsp40 proteins. DnaJA2b,
DnaJB1b, DnaJC2, DnaJC20, and DnaJC21 are named for the first time in this review; all other human DnaJ proteins were dubbed
according to their gene names, e.g. DnaJA1 is the human protein named after its gene DNAJA1. This review highlights the progress
in studying the domains in DnaJ/Hsp40 proteins, introduces the mechanisms by which they interact with Hsp70s, and stresses
their functional diversity.
Received 27 April 2006; received after revision 5 June 2006; accepted 19 July 2006 相似文献