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PubMed1998

Phosphorylation of stathmin modulates its function as a microtubule depolymerizing factor.

Oncoprotein 18 or stathmin was isolated from bovine brain, characterized and novel features of its function as a microtubule depolymerizing factor were tested. The effect of phosphorylation of stathmin on its function as a microtubule depolymerizing factor has been tested in vitro. Five different protein kinases, protein kinase A, MAP kinase, cdc2 kinase, glycogen synthase kinase 3 and casein kinase 2, were used to modify stathmin, since it is known that these kinases could phosphorylate several residues that are modified in vivo and could have important roles in stathmin function. The residues phosphorylated in vitro by the different protein kinases were identified and in some cases they correspond to those modified in vivo. Recombinant unphosphorylated stathmin and native stathmin, which was previously dephosphorylated with alkaline phosphatase, showed similar microtubule depolymerizing activity. This activity is higher than that of stathmin phosphorylated by protein kinase A, MAP kinase or cdc 2 kinase, whereas phosphorylation of the protein with casein kinase 2 or glycogen synthase kinase 3 resulted in a slight increase of the depolymerizing activity.

Animals↗
PubMed2000

Overexpression of stathmin in breast carcinomas points out to highly proliferative tumours.

We recently discovered that stathmin was overexpressed in a subgroup of human breast carcinomas. Stathmin is a cytosolic phosphoprotein proposed to act as a relay integrating diverse cell signalling pathways, notably during the control of cell growth and differentiation. It may also be considered as one of the key regulators of cell division for its ability to destabilize microtubules in a phosphorylation-dependent manner. To assess the significance of stathmin overexpression in breast cancer, we evaluated the correlation of stathmin expression, quantified by reverse transcription polymerase chain reaction, with several disease parameters in a large series of human primary breast cancer (n = 133), obtained in strictly followed up women, whose clinico-pathological data were fully available. In agreement with our preliminary survey, stathmin was found overexpressed in a subgroup of tumours (22%). In addition, overexpression was correlated to the loss of steroid receptors (oestrogen, P = 0.0006; progesterone, P = 0.008), and to the Scarff-Bloom-Richardson histopathological grade III (P= 0.002), this latter being ascribable to the mitotic index component (P= 0.02). Furthermore studies at the DNA level indicated that stathmin is overexpressed irrespective of its genomic status. Our findings raise important questions concerning the causes and consequences of stathmin overexpression, and the reasons of its inability to counteract cell proliferation in the overexpression group.

Adult↗
PubMed1995

Stathmin interaction with a putative kinase and coiled-coil-forming protein domains.

Stathmin is a ubiquitous, cytosolic 19-kDa protein, which is phosphorylated on up to four sites in response to many regulatory signals within cells. Its molecular characterization indicates a functional organization including an N-terminal regulatory domain that bears the phosphorylation sites, linked to a putative alpha-helical binding domain predicted to participate in coiled-coil, protein-protein interactions. We therefore proposed that stathmin may play the role of a relay integrating diverse intracellular regulatory pathways; its action on various target proteins would be a function of its combined phosphorylation state. To search for such target proteins, we used the two-hybrid screen in yeast, with stathmin as a "bait." We isolated and characterized four cDNAs encoding protein domains that interact with stathmin in vivo. One of the corresponding proteins was identified as BiP, a member of the hsp70 heat-shock protein family. Another is a previously unidentified, putative serine/threonine kinase, KIS, which might be regulated by stathmin or, more likely, be part of the kinases controlling its phosphorylation state. Finally, two clones code for subdomains of two proteins, CC1 and CC2, predicted to form alpha-helices participating in coiled-coil interacting structures. Their isolation by interaction screening further supports our model for the regulatory function of stathmin through coiled-coil interactions with diverse downstream targets via its presumed alpha-helical binding domain. The molecular and biological characterization of KIS, CC1, and CC2 proteins will give further insights into the molecular functions and mechanisms of action of stathmin as a relay of integrated intracellular regulatory pathways.

Amino Acid Sequence↗
PubMed1989

Stathmin is a major phosphoprotein and cyclic AMP-dependent protein kinase substrate in mouse brain neurons but not in astrocytes in culture: regulation during ontogenesis.

Stathmin is a ubiquitous soluble protein (Mr approximately 19,000; pI approximately 6.2-5.5) whose phosphorylation is associated with the intracellular mechanisms involved in the regulations of cell differentiation and functions by extracellular effectors. It is present in various tissues and cell types and has several nonphosphorylated and increasingly phosphorylated forms, and it is particularly abundant in brain. Very high concentrations of stathmin were also detected in mouse embryo striatal neurons grown in primary culture, whereas stathmin was barely detectable in astrocytes from the same source. Stathmin appeared in neurons as a major substrate for protein phosphorylation and, in particular, for the cyclic AMP (cAMP)-dependent protein kinase, because its phosphorylation was stimulated by cAMP in cell-free preparations and in intact cells by forskolin, a potent activator of adenylate cyclase. During brain ontogenesis, stathmin was first detected at embryonic day 12; its concentration increased until birth and then decreased from postnatal day 10 to adulthood. In parallel, its molecular forms shifted from the least phosphorylated to the more phosphorylated ones. This result may reflect the evolution of the activity of stathmin during development and the subsequent maturation of the brain. In conclusion, our results substantiate the likely role of stathmin as an intracellular relay of extracellular regulations, as they point out its specific importance related to neuronal functions and brain differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Targeting stathmin in prostate cancer.

Stathmin is the founding member of a family of microtubule-destabilizing proteins that regulate the dynamics of microtubule polymerization and depolymerization. Stathmin is expressed at high levels in a variety of human cancers and provides an attractive molecule to target in cancer therapies that disrupt the mitotic apparatus. We developed replication-deficient bicistronic adenoviral vectors that coexpress green fluorescent protein and ribozymes that target stathmin mRNA. The therapeutic potential of these recombinant adenoviruses was tested in an experimental androgen-independent LNCaP prostate cancer model. Adenovirus-mediated transfer of anti-stathmin ribozymes resulted in efficient transduction and marked inhibition of stathmin expression in these cells. Cells that were transduced with the anti-stathmin adenoviruses showed a dramatic dose-dependent growth inhibition. This was associated with accumulation of LNCaP cells in the G2-M phases of the cell cycle. A similar dose-dependent inhibition of clonogenic potential was also observed in cells infected with anti-stathmin adenoviruses. Morphologic and biochemical analysis of infected cells showed a marked increase in apoptosis characterized by detachment of the cells, increased chromatin condensation, activation of caspase-3, and fragmentation of internucleosomal DNA. If these findings are confirmed in vivo, it may provide an effective approach for the treatment of prostate cancer.

Adenoviridae↗
PubMed2005

Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation.

Physiological polyploidy is a characteristic of several cell types including the megakaryocytes (MK) that give rise to circulating blood platelets. MK achieve polyploidy by switching from a normal to an endomitotic cell cycle characterized by the absence of late mitotic stages. During an endomitotic cycle, the cells enter into mitosis and proceed normally through metaphase and early anaphase. However, late anaphase, telophase and cytokinesis are aborted. This abortive mitosis is associated with atypical multipolar mitotic spindles and limited chromosome segregation. Stathmin is a microtubule-depolymerizing protein that is important for the regulation of the mitotic spindle and interfering with its expression disrupts the normal mitotic spindle and leads to aberrant mitotic exit. As cells enter mitosis, the microtubule depolymerizing-activity of stathmin is switched-off, allowing microtubules to polymerize and assemble into a mitotic spindle. Reactivation of stathmin in the later stages of mitosis is necessary for the disassembly of the mitotic spindle and the exit from mitosis. Previous studies had shown that stathmin expression is downregulated as MK become polyploid and inhibition of its expression in K562 cells increases their propensity to become polyploid. In this report, we describe our studies of the mechanism by which stathmin plays its role in MK polyploidization. We show that stathmin overexpression prevents the transition from a mitotic cycle to an endomitotic cycle as determined by a decrease in the number of multipolar mitotic spindles. These observations support a model in which downregulation of stathmin expression in megakaryocytes and other polyploid cells may be a critically important factor in endomitosis and polyploidy.

Cell Differentiation↗
PubMedDate not supplied

Stathmin expression in immortalized and oncogene transformed cells.

Stathmin is a major cytosolic phosphoprotein that is highly expressed in leukemic cells and many other malignant cell types. The level of stathmin expression in a wide variety of cancer cells suggested that this phosphoprotein may play a role in the process of malignant transformation. We compared the levels of stathmin expression in low passage primary embryonic fibroblasts and in their immortalized counterparts. The immortalized cells had a markedly higher rate of proliferation that was associated with a four fold increase in the level of stathmin expression. In contrast, transformation of the immortalized fibroblasts with seven different activated oncogenes did not result in significant changes in the level of stathmin expression nor in a consistent increase in their rate of proliferation. These observations do not support a direct role for the activation of stathmin gene expression in the transformed phenotype. We suggest that the increased levels of stathmin in transformed cells compared to non-transformed cells may be a reflection of differences in their rate of proliferation and state of differentiation.

Animals↗
PubMed2002

Role of stathmin in the regulation of the mitotic spindle: potential applications in cancer therapy.

Stathmin is a member of a novel class of microtubule-destabilizing proteins that regulate the dynamics of microtubule polymerization and depolymerization. Stathmin promotes microtubule depolymerization during interphase and late mitosis. This microtubule depolymerizing activity of stathmin is regulated by changes in its level of phosphorylation that occur during cell cycle progression. These modifications allow it to play a critical role in the regulation of the dynamic equilibrium of microtubules during different phases of the cell cycle. Stathmin is expressed at high levels in a wide variety of human cancers. Inhibition of stathmin expression in malignant cells interferes with their orderly progression through the cell cycle and abrogates their transformed phenotype. Thus, stathmin provides an attractive molecular target for disrupting the mitotic apparatus and arresting the growth of malignant cells. In this review, we describe the current understanding of the role of stathmin in the regulation of the mitotic spindle and discuss its potential as a therapeutic target of cancer therapy.

Cell Cycle↗
PubMed1995

Stathmin is expressed by the proliferating hepatocytes during liver regeneration.

Aim-To determine the liver cell populations that express the phylogenetically conserved cytosolic protein stathmin during liver regeneration.Methods-Double immunostaining for stathmin and the Ki67 antigen was performed on sections of formaldehyde fixed, paraffin wax embedded tissues from 31 liver specimens. These included a variety of disease conditions characterised by some degree of hepatocyte regeneration. Quantitative western blot analysis was performed on 22 of these specimens.Results-Variable amounts of stathmin protein were detected by western blotting in all of the specimens examined. Stathmin was not detected in three cases of histologically normal liver. On immunostaining, stathmin was demonstrated in a proportion of hepatocytes as well as lymphoid inflammatory cells and other tissue elements. In all cases most of these stathmin positive cells showed nuclear positivity for the Ki67 antigen.Conclusions-Stathmin is expressed by proliferating hepatocytes but not by resting hepatocytes. Thus, it is likely that the protein has a function important to cell proliferation as opposed to cell differentiation.

Journal Article↗
PubMed2001

Expression of SCG10 and stathmin proteins in the rat olfactory system during development and axonal regeneration.

The membrane-associated protein SCG10 is expressed specifically by neuronal cells. Recent experiments have suggested that it promotes neurite outgrowth by increasing microtubule dynamics in growth cones. SCG10 is related to the ubiquitous but neuron-enriched cytosolic protein stathmin. To better understand the role played by SCG10 and stathmin in vivo, we have analyzed the expression and localization of these proteins in both the olfactory epithelium and the olfactory bulb in developing and adult rats, as well as in adult bulbectomized rats. The olfactory epithelium is exceptional in that olfactory receptor neurons constantly regenerate and reinnervate the olfactory bulb throughout animal life-span. SCG10 and stathmin expression in the olfactory receptor neurons was found to be regulated during embryonic and postnatal development and to correlate with neuronal maturation. Whereas SCG10 expression was restricted to immature olfactory receptor neurons (GAP-43-positive, olfactory marker protein-negative), stathmin was also expressed by the basal cells. In the olfactory bulb of postnatal and adult rats, a moderate to strong SCG10 immunoreactivity was present in the olfactory nerve layer, whereas no labeling was detected in the glomerular layer. Olfactory glomeruli also showed no apparent immunoreactivity for several cytoskeletal proteins such as tubulin and microtubule-associated proteins. In unilaterally bulbectomized rats, SCG10 and stathmin were seen to be up-regulated in the regenerating olfactory epithelium at postsurgery stages corresponding to olfactory axon regeneration. Our data strongly suggest that, in vivo, both SCG10 and stathmin may play a role in axonal outgrowth during ontogenesis as well as during axonal regeneration.

Aging↗
PubMed2001

Proteome analysis of rat spermatogonia: reinvestigation of stathmin spatio-temporal expression within the testis.

Stathmin is a protein known to be involved in various cell processes including cell proliferation and differentiation. It has already been described in the testis but its recent identification using a proteomic approach in mitotic spermatogenetic stem cells named spermatogonia (Guillaume et al., 2000) has lead us to reinvestigate its expression within the testis. Stathmin and its mRNAs were studied in isolated cells by Western and Northern blots and in situ using immunohistochemistry. We demonstrated that stathmin is indeed expressed in spermatogonia, and that it is also intensively expressed in the meiotic spermatocytes and in the first generations of spermatids. Furthermore, we showed aggregations of the protein in the cytoplasm of the later generations of spermatids preceding its elimination at the time of spermiation. Our Northern blots reveal the presence of two stathmin transcripts of 1.1 and 3.2 kb within the testis from the fetal stage onwards, in spermatogonia, spermatocytes, and spermatids. However, the 3.2 kb RNA transcript was barely detectable in the spermatids. Stathmin expression is known to be associated with microtubule dynamics. Therefore, its expression in the germ line is most probably related to the extremely complex structural cellular rearrangements occurring in germ cells during spermatogenesis. However, the exact role of stathmin and the reason of the existence of two transcripts in the male germ lineage awaits further investigation.

Animals↗
PubMed1993

Stathmin in mung bean leaves and rat brain.

Stathmin is a highly-conserved, cytosolic protein whose synthesis and phosphorylation is closely associated with growth and differentiation. Although conserved among vertebrates, stathmin has not been identified in plants. In the present study, anti-stathmin antibodies were generated against a synthetic peptide corresponding to amino-acid residues 32-44 of rat stathmin, and these antibodies were used to probe immunoblots of proteins from rat brain and mung bean. The antibodies recognized 12-kDa, 21-kDa and 22-kDa proteins in cytosolic fractions from mung bean leaves and a 12-kDa protein in cytosolic fractions from roots. The two larger proteins identified by the antibodies have apparent molecular weights and isoelectric points similar to those of rat brain stathmin. These results are the first to show that stathmin-like proteins are present in plants.

Amino Acid Sequence↗
PubMed2006

Analysis on heat stress-induced hyperphosphorylation of stathmin at serine 37 in Jurkat cells by means of two-dimensional gel electrophoresis and tandem mass spectrometry.

Two-dimensional gel electrophoresis (2-DE) and tandem mass spectrometry were successfully used for determination of a phosphorylation site of stathmin induced by heat stress to Jurkat cells of a human T lymphoblastic cell line. The cells were incubated for 30 min at 41 degrees C up to 45 degrees C in a serum free 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffered culture medium. The intracellular soluble proteins were separated by 2-DE, and some of the proteins increased their abundance by heat stress. Those proteins were identified to be calmodulin, protein kinase C substrate, thymosin beta-4 and F-actin capping protein beta-subunit by peptide mass fingerprinting (PMF) with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). On the contrary, protein phosphatase 2C gamma-isoform, nucleophosmin, translationally controlled tumor protein, Rho GDP-dissociation inhibitor-1, eukaryotic translation initiation factors 5A and 3A subunit 2, ubiquitin-like protein SMT 3B and chloride intracellular channel protein-1 were decreased their abundance. A protein spot of M(r) 18,000 and pI 5.9 was markedly increased at temperatures higher than 43 degrees C at which the cells were led to apoptosis. The spot was identified to be stathmin of a signal relay protein which has a function of sequestering microtubule. MALDI-quadrupole ion trap (QIT)-TOF-MS/MS and immunoblotting with a monoclonal antibody specific for a phosphorylation site of stathmin showed that the spot was a phosphorylated stathmin at serine 37 (Ser 37). The phosphorylation was suppressed by treatment of cells with olomoucine of an inhibitor specific for cyclin dependent kinase (Cdk-1). These results strongly suggest that heat stress activates Cdk-1 which phosphorylates Ser 37 on the stathmin molecule. The phosphorylation may cause the functional loss of stathmin for dynamic microtubule assembly and leads Jurkat cells to cell cycle arrest and apoptosis.

Amino Acid Sequence↗
PubMed2001

Perforant path lesion induces up-regulation of stathmin messenger RNA, but not SCG10 messenger RNA, in the adult rat hippocampus.

In this study, we performed in situ hybridization analysis of the expression pattern of two growth-associated proteins, stathmin and SCG10, in the hippocampus after unilateral lesion of the perforant pathway, the main excitatory input from the entorhinal cortex to the hippocampus. Stathmin is one of the major neural-enriched cytosolic phosphoproteins and a potential target of cyclic-AMP-dependent kinases [Jin L. W. et al. (1996) Neurobiol. Aging 17, 331-341; Leighton I. A. et al. (1993) Molec. Cell Biochem. 127/128, 151-156]. Three days after the lesion, stathmin messenger RNA was up-regulated ipsilaterally in the hilus, in the granule cell layer of the dentate gyrus and in the pyramidal cell layer of the CA1 region. Simultaneously, the hilar region of the contralateral dentate gyrus showed an increased stathmin messenger RNA expression. This altered expression pattern was observed until 15 days after lesion. Stathmin messenger RNA expression returned to a normal level until 21 days after lesion in all regions analysed. SCG10, a membrane-bound neuronal growth-associated protein belonging to the SCG10/stathmin gene family, did not show any alteration of messenger RNA expression after perforant path lesion. The temporal changes of stathmin messenger RNA expression in the ipsilateral hippocampus correspond well to the process of reactive synaptogenesis. The enhanced messenger RNA expression in the hilar region of the contralateral dentate gyrus might suggest a role in neurite elongation, since this region is the origin of commissural fibres involved in the sprouting response in the deafferented hippocampus. The present study provides evidence that the induction of specific growth-associated proteins is differentially regulated in the hippocampus.

Animals↗
PubMed2003

Expression of stathmin family genes in human tissues: non-neural-restricted expression for SCLIP.

The stathmin family consists of phosphoproteins highly conserved in vertebrates and thought to be implicated in the development and functional regulation of various organs, most notably the nervous system. This family includes stathmin, SCG10, SCLIP, and RB3, phosphoproteins that are related by structural and functional homologies. They all sequester tubulin and interfere with microtubule dynamics, a property due to their shared stathmin-like domain. Little is known about the expression of the stathmin gene family in humans. Herein, we describe for the first time, for a collection of human tissues, the expression of each member of this family, using real-time quantitative RT-PCR. We found that stathmin is ubiquitously expressed, whereas SCG10 and RB3 are neural enriched, expression patterns similar to those reported for other mammals. Surprisingly, SCLIP, whose expression is thought to be neural-specific, exhibits a broader tissue distribution. Analyses of the SCLIP gene (approved symbol STMN3) show that it contains several NRSE-like elements that display low or no affinity for the cognate binding protein NRSF. The substantial expression of SCLIP in most tissues points out a novel function for this protein outside the nervous system and raises the possibility that its coexpression with stathmin could provide some degree of functional redundancy.

Antibodies, Monoclonal↗
PubMed2003

Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells.

Two paclitaxel(Ptx)-resistant ovarian cancer cell lines, 1A9/Ptx-10 and 1A9/Ptx-22, isolated from the 1A9 cell line (a clone of the A2780 line) by continuous exposure to Ptx and verapamil, have point mutations in their major beta-tubulin gene and in one or both alleles of their TP53 gene. These cells were examined for alterations in cell cycle regulators and the tubulin-binding protein stathmin. Unlike parental cells, neither 1A9/Ptx-10 nor 1A9/Ptx-22 expressed detectable levels of p21(WAF1/Cip1), a putative transcriptional regulator of stathmin, but did overexpress stathmin and Bcl2. No differences were noted in the expression levels of proliferative cell nuclear antigen or tyrosine-phosphorylated p34Cdc2. Ptx treatment altered little the expression of stathmin in the parental cell line, although it increased p21(WAF1/Cip1) levels several-fold. Infection of Ptx-resistant lines with a wild-type TP53-bearing adenovirus (AdWTp53) changed cell cycle distribution and increased the levels of p21(WAF1/Cip1), but caused no changes in stathmin levels. Microtubule drug resistance in ovarian carcinoma may be associated with altered p53/21(WAF1/Cip1) regulatory pathways for stathmin expression and function.

Animals↗
PubMed2006

Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin.

Stat3 is a member of the signal transducer and activator of transcription family, which is important in cytokine signaling. Gene ablation studies have revealed a requirement for Stat3 in diverse biological processes (Akira, S. 2000. Oncogene. 19: 2607-2611; Levy, D.E., and C.K. Lee. 2002. J. Clin. Invest. 109:1143-1148). Previously, the function of Stat3 had been attributed exclusively to its transcriptional activity in the nucleus. In this study, we reveal an interaction between Stat3 and the microtubule (MT)-destabilizing protein stathmin. Stathmin did not overtly affect ligand-stimulated Stat3 activation. In contrast, the expression of Stat3 is required for the stabilization of MTs and cell migration. We further demonstrate that Stat3-containing cells are resistant to the MT-destabilizing effect of stathmin overexpression. In addition, down-regulation of stathmin protein levels in Stat3-deficient cells partially reversed the MT and migration deficiencies. Recombinant Stat3 was also capable of reversing stathmin inhibition of tubulin polymerization in vitro. Our results indicate that Stat3 modulates the MT network by binding to the COOH-terminal tubulin-interacting domain of stathmin and antagonizing its MT destabilization activity.

Animals↗
PubMed2004

Proteomic and immunochemical characterization of a role for stathmin in adult neurogenesis.

Stathmin is a developmentally regulated cytosolic protein expressed at high levels in the brain. Two-dimensional differential in-gel electrophoresis and mass spectroscopy of proteins expressed in immature and mature cultures from embryonic rat cerebral cortex identified stathmin among several differentially expressed proteins, consistent with a possible role in neurogenesis. Stathmin immunohistochemistry in adult rodent brain revealed prominent expression in neuroproliferative zones and neuronal migration pathways, a pattern that resembles the expression of doublecortin, which is implicated in neuronal migration. Stathmin immunoreactivity was also associated with neurons undergoing ectopic chain migration into the ischemic striatum and cerebral cortex following focal cerebral ischemia. Reducing the expression of stathmin or doublecortin with an antisense oligonucleotide inhibited the migration of new neurons from the subventricular zone to the olfactory bulb via the rostral migratory stream. These results suggest a role for stathmin in the migration of newborn neurons in the adult brain.

Aging↗