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At least 127 records · Page 7Linked to original sources
PubMed1998

Analysis of heat shock-induced monophosphorylation of stathmin in human T lymphoblastic cell line JURKAT by two-dimensional gel electrophoresis.

Two-dimensional gel electrophoresis (2-DE) was used to study alterations in intracellular proteins of the human T lymphoblastic cell line JURKAT by heat shock at 45 degrees C for 30 min. The 2-DE patterns indicated an increase in the amount of a spot of molecular weight (M(r)) 18,500 and isoelectric point (pI) 5.6, which was a monophosphorylated form of stathmin. Stathmin is a major substrate for a proline-rich peptide-specific serine protein kinase, a mitogen-activated protein kinase, however, the enzyme was not activated by the heat shock. Further examinations of the effects of cAMP, phorbol myristate acetate, cyclosporin A, and staurosporine on phosphorylation suggest that cyclin-dependent kinases might be responsible for the heat shock-induced monophosphorylation of stathmin.

Amino Acid Sequence↗
PubMed2004

Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth.

The related proteins SCG10 and stathmin are highly expressed in the developing nervous system. Recently it was discovered that they are potent microtubule destabilizing factors. While stathmin is expressed in a variety of cell types and shows a cytosolic distribution, SCG10 is neuron-specific and membrane-associated. It contains an N-terminal targeting sequence that mediates its transport to the growing tips of axons and dendrites. SCG10 accumulates in the central domain of the growth cone, a region that also contains highly dynamic microtubules. These dynamic microtubules are known to be important for growth cone advance and responses to guidance cues. Because overexpression of SCG10 strongly enhances neurite outgrowth, SCG10 appears to be an important factor for the dynamic assembly and disassembly of growth cone microtubules during axonal elongation. Phosphorylation negatively regulates the microtubule destabilizing activity of SCG10 and stathmin, suggesting that these proteins may link extracellular signals to the rearrangement of the neuronal cytoskeleton. A role for these proteins in axonal elongation is also supported by their growth-associated expression pattern in nervous system development as well as during neuronal regeneration.

Animals↗
PubMed1991

Stathmin phosphorylation patterns discriminate between distinct transduction pathways of human T lymphocyte activation through CD2 triggering.

CD2 triggering of human T lymphocyte activation has been associated with the activation of different interacting protein kinases, including protein kinase C (PKC). However the precise roles of its phosphorylated substrates are still unknown. We show here that PKC-dependent and -independent pathways are responsible for the CD2-induced phosphorylation of stathmin, a ubiquitous soluble phosphoprotein, most likely acting as a general intracellular relay integrating various second messenger pathways. The phosphorylated variants of stathmin provide a fingerprint reflecting the second messenger pathway(s) stimulated. The respective roles of both PKC and stathmin in the regulation of T lymphocyte proliferation are discussed.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2005

p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion.

Emerging evidences suggest that cyclin-dependent kinase inhibitors (CKIs) can regulate cellular functions other than cell cycle progression, such as differentiation and migration. Here, we report that cytoplasmic expression of p27(kip1) affects microtubule (MT) stability following cell adhesion on extracellular matrix (ECM) constituents. This p27(kip1) activity is due to its ability to bind and impair the function of the MT-destabilizing protein stathmin. Accordingly, upregulation of p27(kip1) or downregulation of stathmin expression results in the inhibition of mesenchymal cell motility. Moreover, high stathmin and low cytoplasmic p27(kip1) expression correlate with the metastatic phenotype of human sarcomas in vivo. This study provides a functional link between proliferation and invasion of tumor cells based on diverse activities of p27(kip1) in different subcellular compartments.

Animals↗
PubMed2005

p27(Kip1) and stathmin share the stage for the first time.

Cell migration is essential for development, morphogenesis, tissue repair and tumor metastasis. p27(Kip1) and stathmin are two cell-cycle-regulatory proteins that were recently shown to play important roles in the regulation of cell migration. In this article, we discuss a new study that places p27(Kip1) and stathmin in the same pathway by showing that stathmin, a microtubule-regulatory protein, mediates the effects of p27(Kip1) on cell motility. These findings provide new insights into migration and metastasis of tumor cells and the relationship of these processes to cell proliferation.

Animals↗
PubMed2000

The SCG10-related gene family in the developing rat retina: persistent expression of SCLIP and stathmin in mature ganglion cell layer.

Neuronal growth-associated proteins (GAPs), such as GAP-43 and SCG10, are thought to play crucial roles in both axonal and dendritic outgrowth during neural development and regeneration, although the underlying mechanisms remain largely unknown. The recent finding that SCG10 is a microtubule regulator and also the identification of RB3 and SCLIP as two new SCG10-related members prompted us to investigate the roles of SCG10-related family in neural development, using the retina as a model system. We determined the temporal expression and the spatial distribution of SCG10-related mRNAs in the developing rat retina. Semiquantitative analysis by RT-PCR revealed that in prenatal retina, levels of SCG10 and stathmin mRNAs were higher than those of RB3 and SCLIP. In the postnatal retina, the level of SCLIP increased, whereas the level of RB3 remained low. In situ hybridization revealed that GAP-43 and all of the SCG10-related family mRNAs were present in the retinal ganglion cells (RGCs) at all stages of retinal development, and that stathmin mRNA was present in mitotic neuroblastic cells. Differential expression of SCG10 and other members of the family became more evident as retinal development proceeded; SCG10 and RB3 expression were relatively specific in the RGCs and amacrine cells, whereas SCLIP was also evident in bipolar and horizontal cells. Stathmin mRNA was highly expressed both in the RGCs and other interneurons. These results indicate that multiple SCG10-related proteins are expressed in single neurons including RGCs, and suggest that these nGAPs play similar but distinct roles in differentiation and functional maintenance of retinal neurons.

Animals↗
PubMed2005

N-terminal stathmin-like peptides bind tubulin and impede microtubule assembly.

Microtubules are major cytoskeletal components involved in numerous cellular functions such as mitosis, cell motility, or intracellular traffic. These cylindrical polymers of alphabeta-tubulin assemble in a closely regulated dynamic manner. We have shown that the stathmin family proteins sequester tubulin in a nonpolymerizable ternary complex, through their stathmin-like domains (SLD) and thus contribute to the regulation of microtubule dynamics. We demonstrate here that short peptides derived from the N-terminal part of SLDs impede tubulin polymerization with various efficiencies and that phosphorylation of the most potent of these peptides reduces its efficiency as in full-length stathmin. To understand the mechanism of action of these peptides, we undertook a NMR-based structural analysis of the peptide-tubulin interaction with the most efficient peptide (I19L). Our results show that, while disordered when free in solution, I19L folds into a beta-hairpin upon binding to tubulin. We further identified, by means of saturation transfer difference NMR, hydrophobic residues located on the beta2-strand of I19L that are involved in its tubulin binding. These structural data were used together with tubulin atomic coordinates from the tubulin/RB3-SLD crystal structure to model the I19L/tubulin interaction. The model agrees with I19L acting through an autonomous tubulin capping capability to impede tubulin polymerization and provides information to help understand the variation of efficiency against tubulin polymerization among the peptides tested. Altogether these results enlighten the mechanism of tubulin sequestration by SLDs, while they pave the way for the development of protein-based compounds aimed at interfering with tubulin polymerization.

Amino Acid Sequence↗
PubMed2002

E2F mediates sustained G2 arrest and down-regulation of Stathmin and AIM-1 expression in response to genotoxic stress.

Exposure of cells to genotoxic agents results in activation of checkpoint pathways leading to cell cycle arrest. These arrest pathways allow repair of damaged DNA before its replication and segregation, thus preventing accumulation of mutations. The tumor suppressor retinoblastoma (RB) is required for the G(1)/S checkpoint function. In addition, regulation of the G(2) checkpoint by the tumor suppressor p53 is RB-dependent. However, the molecular mechanism underlying the involvement of RB and its related proteins p107 and p130 in the G(2) checkpoint is not fully understood. We show here that sustained G(2)/M arrest induced by the genotoxic agent doxorubicin is E2F-dependent and involves a decrease in expression of two mitotic regulators, Stathmin and AIM-1. Abrogation of E2F function by dominant negative E2F abolishes the doxorubicin-induced down-regulation of Stathmin and AIM-1 and leads to premature exit from G(2). Expression of the E7 papilloma virus protein, which dissociates complexes containing E2F and RB family members, also prevents the down-regulation of these mitotic genes and leads to premature exit from G(2) after genotoxic stress. Furthermore, genotoxic stress increases the levels of nuclear E2F-4 and p130 as well as their in vivo binding to the Stathmin promoter. Thus, functional complexes containing E2F and RB family members appear to be essential for repressing expression of critical mitotic regulators and maintaining the G(2)/M checkpoint.

3T3 Cells↗
PubMed1997

The cytosolic phosphoprotein stathmin is expressed in the olfactory system of the adult rat.

Stathmin is a cytosolic protein expressed particularly in the developing nervous system, whose phosphorylation is correlated with the action of multiple extracellular stimuli regulating cell proliferation and differentiation. In this study, we used an antibody that specifically recognizes the carboxyterminal region of stathmin to analyze the distribution of this protein in the olfactory system of adult rats, and found a high and selective immunoreactivity in immature olfactory receptors of the olfactory neuroepithelium and in cells of the rostral migratory stream. These results reveal an expression of stathmin in regions of the adult nervous system characterized by striking structural plasticity and cell renewal, suggesting that this protein could play a role in the differentiation of newly generated cell populations.

Animals↗
PubMed2005

PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells.

Increased amounts of reactive oxygen species (ROS) induce apoptosis in mammalian cells. PUMA (P53 up-regulated modulator of apoptosis), a mitochondrial proapoptotic BH3-only protein, induces rapid apoptosis through a Bax- and mitochondria-dependent pathway. However, the molecular basis of PUMA-induced apoptosis is largely not understood. Using a combination of biophysical and biochemical methods and PUMA-inducible colorectal cells, DLD-1.PUMA, we showed that (a) PUMA-induced apoptosis is dose and time dependent; (b) PUMA-induced apoptosis is directly associated with ROS generation; (c) diphenyleneiodonium chloride, a ROS blocker, or BAX-inhibiting peptide, a suppressor of BAX translocation, decreased ROS generation and apoptosis in DLD-1.PUMA cells; (d) overexpression of PUMA induced up-regulation (>1.34-fold) of peroxiredoxin 1 and down-regulation (by 25%) of stathmin through proteasome-mediated degradation; and (e) hydrogen peroxide down-regulated stathmin and disrupted the cellular microtubule network. Our findings indicate that PUMA induces apoptosis, in part, through the BAX-dependent generation of superoxide and hydrogen peroxide. ROS overproduction and oxidative stress induce proteome-wise alterations, such as stathmin degradation and disorganization of the cell microtubule network, in apoptotic cells.

Apoptosis↗
PubMed2005

Two separate motifs cooperate to target stathmin-related proteins to the Golgi complex.

The appropriate targeting of membrane-associated proteins involves a diversity of motifs including post-translational modifications and specific protein sequences. Phosphoproteins of the stathmin family are important regulators of microtubule dynamics, in particular in the developing and mature nervous system. Whereas stathmin is cytosolic, SCG10, SCLIP and the splice variants RB3/RB3'/RB3'' are associated with Golgi and vesicular membranes, through their palmitoylated N-terminal A domains. In order to identify essential motifs involved in this specific targeting, we examined the subcellular distribution of various subdomains derived from domain A of SCG10 fused with GFP. We show that the Golgi localization of SCG10 results from the cooperation of two motifs: a membrane-anchoring palmitoylation motif and a newly identified Golgi-specifying sequence. The latter displayed no targeting activity by itself, but retained a Golgi-specifying activity when associated with another membrane-anchoring palmitoylation motif derived from the protein GAP-43. We further identified critical residues for the specific Golgi targeting of domain A. Altogether, our results give new insight into the regulation of the subcellular localization of stathmin family proteins, an important feature of their physiological functions in differentiating and mature neural cells. More generally we provide new information on essential mechanisms of functional protein subcellular targeting.

Amino Acid Motifs↗
PubMed1999

Differential expression of stathmin during neoplastic conversion of human prostate epithelial cells is reversed by hypomethylating agent, 5-azacytidine.

In a variety of human tumor tissues, including those of prostate and breast, CpG hypermethylation represents one of the mechanisms downregulating the expression of specific proteins, including tumor suppressor proteins. Using 267B1-XR cells generated by ionizing radiation-induced transformation of epithelial cells, derived from neonatal human prostate and immortalized by SV40 (267B1), we now report markedly low levels of expression of the cytoplasmic phosphoprotein stathmin, in addition to several proteins of the actin microfilaments and intermediate filaments that characterize the altered phenotype. Stathmin is emerging as a relay protein integrating signals from diverse pathways during differentiation and neoplastic progression. In this in vitro prostate carcinogenesis model system, where loss of specific-protein expression is a major feature of the transformed 267B1-XR cells, we employed 5-azacytidine treatment followed by 2D-PAGE to reveal if experimental genomic hypomethylation reinstated the levels of any of the differentially expressed proteins. Our data suggest that stathmin represents one such example.

Antimetabolites, Antineoplastic↗
PubMed2000

Taxol and anti-stathmin therapy: a synergistic combination that targets the mitotic spindle.

Stathmin is an abundant cytosolic phosphoprotein that plays an important role in the regulation of cellular proliferation. Its major function is to promote depolymerization of the microtubules that make up the mitotic spindle. Taxol is an effective chemotherapeutic agent whose activity is mediated through stabilization of the microtubules of the mitotic spindle. We demonstrate that antisense inhibition of stathmin expression chemosensitizes K562 leukemic cells to the antitumor effects of Taxol and results in a synergistic inhibition of their growth and clonogenic potential. In the presence of stathmin inhibition, exposure to Taxol results in more severe mitotic abnormalities (hypodiploidy and multinucleation). This, in turn, results in increased apoptosis of the aneuploid cells during subsequent cell division cycles. This novel molecular-based therapeutic approach may provide an effective form of cancer therapy that would avoid the severe toxicities associated with the use of multiple chemotherapeutic agents with overlapping toxicity profiles.

Apoptosis↗
PubMed1993

Epidermal growth factor induces serine phosphorylation of stathmin in a human colon carcinoma cell line (LIM 1215).

Changes in protein phosphorylation in the human colon carcinoma cell line LIM 1215 after stimulation with epidermal growth factor (EGF) have been analyzed by two-dimensional gel electrophoresis and phosphoamino acid analysis. In addition to a number of tyrosine-phosphorylated proteins, a family of small proteins (M(r) 19,000-20,000) is maximally phosphorylated on serine within 5 min of EGF stimulation. One member of the family has been purified by a combination of two-dimensional electrophoresis and reversed-phase high performance liquid chromatography and identified by amino acid sequence analysis as stathmin. Although phosphorylation of stathmin has been reported previously in leukemia cells and following stimulation of hemopoietic or lymphoid cells with several mitogenic agents, this is the first report of stathmin phosphorylation in response to EGF.

Amino Acid Sequence↗
PubMed1995

Induction of stathmin expression during erythropoietic differentiation.

Stathmin is a M(r) 19,000 cytosolic protein proposed to act as a relay for signal-activating pathways regulating cell proliferation and differentiation. In a study of erythropoietic differentiation, stathmin was detected as a protein that is induced during the early stages of differentiation in several cellular model systems. The unphosphorylated form of stathmin was most prominently induced, which suggests that this form does not only play a role in pathways oriented toward cell proliferation, as is the case for lymphocytic systems, but may also play a role in various differentiation pathways.

Amino Acid Sequence↗
PubMed2004

Modulation of the stathmin-like microtubule destabilizing activity of RB3, a neuron-specific member of the SCG10 family, by its N-terminal domain.

RB3 is a neuron-specific homologue of the SCG10/stathmin family proteins, possessing a unique N-terminal membrane-associated domain and the stathmin-like domain at the C terminus, which promotes microtubule (MT) catastrophe and/or tubulin sequestering. We examined herein the contribution of the N-terminal subdomain of RB3 to the regulation of MT dynamics. To begin with, we determined the effects of full-length (RB3-f) and short truncated (RB3-s) forms of RB3 on the polymerization of MT in vitro. RB3-s had a deletion of amino acids 1-75 from the N terminus, leaving the so-called stathmin-like domain, consisting of residues 76-217. Although both RB3-f and RB3-s exhibited MT-depolymerizing activity, RB3-f was less effective. The binding affinity for tubulin was also lower in RB3-f. Direct observation of the dynamics of individual MTs using dark field microscopy revealed that RB3-s slowed MT elongation velocity, increased catastrophes, and reduced rescues. This effect is almost identical to that by stathmin/oncoprotein 18. On the other hand, the MT elongation rate increased at lower concentrations of RB3-f. In addition, RB3-f, indicated higher rescue frequency than control as well as the catastrophe in a dose-dependent manner. The functionality of RB3-f indicated that full-length RB3 has not only stathmin-like MT destabilizing activity but also MT-associated protein-like MT stabilizing activity. Possibly, the balance of these activities is altered in a concentration-dependent manner in vitro. This interesting regulatory role of the unique N-terminal domain of RB3 in MT dynamics would contribute to the physiological regulation of neuronal morphogenesis.

Animals↗
PubMed2002

Electrophoretic studies on the phosphorylation of stathmin and mitogen-activated protein kinases in neuronal cell death induced by oxidized very-low-density lipoprotein with apolipoprotein E.

In the central nervous system, stressful conditions can easily cause the oxidation of lipoprotein particles, followed by the oxidative modification of apolipoproteins such as apolipoprotein E (apoE) and the production of free radicals and aldehydes. We have confirmed that oxidized very-low-density lipoprotein (VLDL) inhibits the proliferation, viability and differentiation of neuronal PC12 cells leading to cell death. The cells internalized intact apoE, but did not internalize oxidized apoE. The phosphorylation of stathmin and various mitogen-activated protein (MAP) kinases including extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) was examined in PC12 cells exposed to native and oxidized VLDL, H(2)O(2) (which generates free radicals), and 4-hydroxy-2-nonenal (HNE) (an aldehyde). Oxidized VLDL and H(2)O(2) reduced stathmin phosphorylation while HNE increased it, suggesting that oxidized VLDL and H(2)O(2) stimulated similar signal transduction pathways. Based on the results, free radicals, but not aldehydes may play a major role in the neuronal cell death induced by lipoprotein oxidation. Furthermore, the phosphorylation status of MAP kinases indicated that the activation of the JNK cascade might be required for neuronal cell death.

Animals↗
PubMed1995

Differential expression of nucleophosmin and stathmin in human T lymphoblastic cell lines, CCRF-CEM and JURKAT analyzed by two-dimensional gel electrophoresis.

Two-dimensional gel electrophoresis was used to study the expression of intracellular proteins in adherent cells of human T lymphoblastic cell line, CCRF-CEM. The adherent cells grown in monolayer on a culture plate decreased the amount of proteins of M(r) 37,000 and pI 4.7-4.9, and of 17,000 and pI 5.7. The proteins were identified to be nucleophosmin for the 37,000 protein and stathmin for the 17,000 protein by microsequencing their CNBr fragments. The amount of proteins was increased in CCRF-CEM cells grown in floating mass to a comparable level of JURKAT cells which grew in floating mass throughout the culture. The adherent cells decreased their growth rate as compared with the cells in the floating mass. These results suggest that the adhesion of human T lymphoblastic cells modulates their morphology and proliferation via a concomitant decrease in the amount of nucleophosmin and stathmin.

Amino Acid Sequence↗