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André Sobel - One of the best experts on this subject based on the ideXlab platform.

  • Neuronal Stathmins: A family of phosphoproteins cooperating for neuronal development, plasticity and regeneration
    Progress in Neurobiology, 2014
    Co-Authors: Stéphanie Chauvin, André Sobel
    Abstract:

    Abstract Nervous system development, plasticity and regeneration require numerous, coordinated and finely tuned subcellular mechanisms. Phosphoproteins of the Stathmin family, originally identified as intracellular signal relay proteins, are mostly or exclusively expressed in the nervous system with a high level of expression during brain development. Vertebrate Stathmins 1–4 all possess a C-terminal “Stathmin-like domain” that binds or releases tubulin in a phosphorylation dependent way, and hence participates in the control of microtubule dynamics, an essential process for neuronal differentiation. Contrary to Stathmin 1, Stathmins 2–4 possess an N-terminal extension whose reversible palmitoylation specifically targets them to the Golgi and intracellular membranes. Regulation of Stathmins 2–4 palmitoylation is therefore an important regulatory mechanism that controls their shuttling to various neuronal compartments where they can then act locally. Expression of Stathmins is upregulated during neuronal differentiation and plasticity, and altered in numerous neurodegenerative diseases. Experimental perturbation of Stathmins expression in Drosophila or in neurons in culture revealed their importance in neuronal growth and differentiation, each Stathmin fulfilling at least partially distinct and likely complementary roles. On the other hand, knock-out of Stathmins in mice, with the exception of Stathmin 2, resulted in mostly mild or no detected phenotype, revealing likely compensations among Stathmins. Altogether, through their combinatorial expression and regulation by phosphorylation and by palmitoylation, and through their interactions with tubulin and other neuronal protein targets, the various Stathmins appear as essential regulators of neuronal differentiation at the various stages during development and plasticity of the nervous system.

  • Drosophila Stathmins bind tubulin heterodimers with high and variable stoichiometries
    Journal of Biological Chemistry, 2010
    Co-Authors: Sylvie Lachkar, Marion Lebois, Michel O. Steinmetz, Antoine Guichet, Patrick A. Curmi, André Sobel, Sylvie Ozon
    Abstract:

    In vertebrates, Stathmins form a family of proteins possessing two tubulin binding repeats (TBRs), which each binds one soluble tubulin heterodimer. The Stathmins thus sequester two tubulins in a phosphorylation-dependent manner, providing a link between signal transduction and microtubule dynamics. In Drosophila, we show here that a single Stathmin gene (stai) encodes a family of D-Stathmin proteins. Two of the D-Stathmins are maternally deposited and then restricted to germ cells, and the other two are detected in the nervous system during embryo development. Like in vertebrates, the nervous system-enriched Stathmins contain an N-terminal domain involved in subcellular targeting. All the D-Stathmins possess a domain containing three or four predicted TBRs, and we demonstrate here, using complementary biochemical and biophysical methods, that all four predicted TBR domains actually bind tubulin. D-Stathmins can indeed bind up to four tubulins, the resulting complex being directly visualized by electron microscopy. Phylogenetic analysis shows that the presence of regulated multiple tubulin sites is a conserved characteristic of Stathmins in invertebrates and allows us to predict key residues in Stathmin for the binding of tubulin. Altogether, our results reveal that the single Drosophila Stathmin gene codes for a Stathmin family similar to the multigene vertebrate one, but with particular tubulin binding properties.

  • drosophila Stathmin a microtubule destabilizing factor involved in nervous system formation
    Molecular Biology of the Cell, 2002
    Co-Authors: Sylvie Ozon, Antoine Guichet, Olivier Gavet, Siegfried Roth, André Sobel
    Abstract:

    Stathmin is a ubiquitous regulatory phosphoprotein, the generic element of a family of neural phosphoproteins in vertebrates that possess the capacity to bind tubulin and interfere with microtubule dynamics. Although Stathmin and the other proteins of the family have been associated with numerous cell regulations, their biological roles remain elusive, as in particular inactivation of the Stathmin gene in the mouse resulted in no clear deleterious phenotype. We identified Stathmin phosphoproteins in Drosophila, encoded by a unique gene sharing the intron/exon structure of the vertebrate Stathmin and Stathmin family genes. They interfere with microtubule assembly in vitro, and in vivo when expressed in HeLa cells. Drosophila Stathmin expression is regulated during embryogenesis: it is high in the migrating germ cells and in the central and peripheral nervous systems, a pattern resembling that of mammalian Stathmin. Furthermore, RNA interference inactivation of Drosophila Stathmin expression resulted in germ cell migration arrest at stage 14. It also induced important anomalies in nervous system development, such as loss of commissures and longitudinal connectives in the ventral cord, or abnormal chordotonal neuron organization. In conclusion, a single Drosophila gene encodes phosphoproteins homologous to the entire vertebrate Stathmin family. We demonstrate for the first time their direct involvement in major biological processes such as development of the reproductive and nervous systems.

  • Stathmin family proteins display specific molecular and tubulin binding properties
    Journal of Biological Chemistry, 2001
    Co-Authors: Elodie Charbaut, Sylvie Lachkar, Patrick A. Curmi, Sylvie Ozon, Virginie Redeker, André Sobel
    Abstract:

    Abstract Stathmin family phosphoproteins (Stathmin, SCG10, SCLIP, and RB3/RB3′/RB3") are involved in signal transduction and regulation of microtubule dynamics. With the exception of Stathmin, they are expressed exclusively in the nervous system, where they display different spatio-temporal and functional regulations and hence play at least partially distinct and possibly complementary roles in relation to the control of development, plasticity, and neuronal activities. At the molecular level, each possesses a specific “Stathmin-like domain” and, with the exception of Stathmin, various combinations of N-terminal extensions involved in their association with intracellular membrane compartments. We show here that each Stathmin-like domain also displays specific biochemical and tubulin interaction properties. They are all able to sequester two α/β tubulin heterodimers as revealed by their inhibitory action on tubulin polymerization and by gel filtration. However, they differ in the stabilities of the complexes formed as well as in their interaction kinetics with tubulin followed by surface plasmon resonance as follows: strong stability and slow kinetics for RB3; medium for SCG10, SCLIP, and Stathmin; and weak stability and rapid kinetics for RB3′. These results suggest that the fine-tuning of their Stathmin-like domains contributes to the specific functional roles of Stathmin family proteins in the regulation of microtubule dynamics within the various cell types and subcellular compartments of the developing or mature nervous system.

  • Stathmin/Op18 Phosphorylation Is Regulated by Microtubule Assembly
    Molecular Biology of the Cell, 2001
    Co-Authors: Thomas Küntziger, André Sobel, Olivier Gavet, Valérie Manceau, Michel Bornens
    Abstract:

    Stathmin/Op 18 is a microtubule (MT) dynamics-regulating protein that has been shown to have both catastrophe-promoting and tubulin-sequestering activities. The level of Stathmin/Op18 phosphorylation was proved both in vitro and in vivo to be important in modulating its MT-destabilizing activity. To understand the in vivo regulation of Stathmin/Op18 activity, we investigated whether MT assembly itself could control phosphorylation of Stathmin/Op18 and thus its MT-destabilizing activity. We found that MT nucleation by centrosomes from Xenopus sperm or somatic cells and MT assembly promoted by dimethyl sulfoxide or paclitaxel induced Stathmin/Op18 hyperphosphorylation in Xenopus egg extracts, leading to new Stathmin/Op18 isoforms phosphorylated on Ser 16. The MT-dependent phosphorylation of Stathmin/Op18 took place in interphase extracts as well, and was also observed in somatic cells. We show that the MT-dependent phosphorylation of Stathmin/Op18 on Ser 16 is mediated by an activity associated to the MTs, and that it is responsible for the Stathmin/Op18 hyperphosphorylation reported to be induced by the addition of “mitotic chromatin.” Our results suggest the existence of a positive feedback loop, which could represent a novel mechanism contributing to MT network control.

Jone Trovik - One of the best experts on this subject based on the ideXlab platform.

  • Stathmin protein level a potential predictive marker for taxane treatment response in endometrial cancer
    PLOS ONE, 2014
    Co-Authors: Even Birkeland, Jone Trovik, Henrica M J Werner, Mari K Halle, Lars A Akslen, Therese Bredholt, Ingvild L Tangen
    Abstract:

    Stathmin is a prognostic marker in many cancers, including endometrial cancer. Preclinical studies, predominantly in breast cancer, have suggested that Stathmin may additionally be a predictive marker for response to paclitaxel. We first evaluated the response to paclitaxel in endometrial cancer cell lines before and after Stathmin knock-down. Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in metastatic endometrial cancer in relation to Stathmin protein level in tumors. Stathmin level was also determined in metastatic lesions, analyzing changes in biomarker status on disease progression. Knock-down of Stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. In clinical samples, high Stathmin level was demonstrated to be associated with poor response to paclitaxel containing chemotherapy and to reduced disease specific survival only in patients treated with such combination. Stathmin level increased significantly from primary to metastatic lesions. This study suggests, supported by both preclinical and clinical data, that Stathmin could be a predictive biomarker for response to paclitaxel treatment in endometrial cancer. Re-assessment of Stathmin level in metastatic lesions prior to treatment start may be relevant. Also, validation in a randomized clinical trial will be important.

  • high phospho Stathmin serine38 expression identifies aggressive endometrial cancer and suggests an association with pi3k inhibition
    Clinical Cancer Research, 2013
    Co-Authors: Even Birkeland, Jone Trovik, Henrica M J Werner, Erling A Hoivik, Siv Mjos, Camilla Krakstad, Kanthida Kusonmano, Karen Klepsland Mauland, Ingunn Stefansson, Frederik Holst
    Abstract:

    Purpose: High Stathmin expression has recently been associated with clinical progress in endometrial cancers. Stathmin protein activity is modulated by phosphorylation, and the Serine38 site is one of four Stathmin phospho-sites. The presence and significance of pStathmin(S38) is largely unknown in human cancers, and we here examined the associations between this marker and tumor cell proliferation, clinicopathologic phenotype, and survival impact in endometrial cancer. A relationship with possible treatment targets was explored by integrated analysis of transcriptional alterations. Experimental Design: Primary endometrial cancers from two independent patient series ( n = 518/ n = 286) were analyzed. Biomarkers were assessed by immunohistochemistry, FISH, flow cytometry, DNA oligonucleotide microarray, single-nucleotide polymorphism array, and Sanger sequencing, and related to clinicopathologic annotations and follow-up information. Results: High pStathmin(S38) level was associated with poor prognosis, independent of other features, and correlated to increased tumor cell proliferation as well as high Stathmin levels. On the basis of transcriptional differences between high/low pStathmin(S38) tumors, phosphoinositide 3-kinase (PI3K)/mTOR/HSP90 were suggested as possible targets in pStathmin(S38)-high cases. High pStathmin(S38) was associated with several PI3K pathway alterations: amplification of the 3q26 region, increased PIK3CA copy number (FISH) and a PI3K activation score (all P Conclusions: High pStathmin(S38) is a novel biomarker of increased tumor cell proliferation and impaired prognosis as reported here for independent cohorts of endometrial cancer and not previously shown in human cancer. Our data support a rationale for further studies exploring effects of drugs inhibiting the PI3K signaling pathway in pStathmin(S38)-high endometrial cancer, including a potential value of pStathmin(S38) in predicting response to PI3K/mTOR/HSP90 inhibitors. Clin Cancer Res; 19(9); 2331–41. ©2013 AACR .

  • Stathmin overexpression identifies high risk patients and lymph node metastasis in endometrial cancer
    Clinical Cancer Research, 2011
    Co-Authors: Jone Trovik, Ingunn Stefansson, Lars A Akslen, Janusz Marcickiewicz, Solveig Tingulstad, Anne Cathrine Staff, Tormund S Njolstad, Ingrid Vandenput, Frederic Amant, Helga B Salvesen
    Abstract:

    Purpose: Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis. Experimental Design: A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival. Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens. Results: Seventy-one percent of the patients ( n = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes ( n = 94). Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases. High Stathmin expression was associated with poor disease-specific survival ( P ≤ 0.002) both in curettage and hysterectomy specimens. Conclusions: Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined. Clin Cancer Res; 17(10); 3368–77. ©2011 AACR .

Laiping Zhong - One of the best experts on this subject based on the ideXlab platform.

  • Stathmin guides personalized therapy in oral squamous cell carcinoma.
    Cancer Science, 2020
    Co-Authors: Wu‐tong Ju, Lizhen Wang, Zhiyuan Zhang, Hailong Ma, Tong-chao Zhao, Si-yuan Liang, Jiang Li, Ge Zhou, Laiping Zhong
    Abstract:

    The survival benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy in oral squamous cell carcinoma (OSCC) patients is not satisfactory. Previously, we identified that Stathmin, a microtubule-destabilizing protein, is overexpressed in OSCC. Here, we further investigated its role as a biomarker that impacts on OSCC chemosensitivity. We analyzed the predictive value of Stathmin on TPF induction chemotherapy and its impact on OSCC cell chemosensitivity. Then, we further investigated the therapeutic effects of the combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors in vitro and in vivo. We found that OSCC patients with low Stathmin expression benefited from TPF induction chemotherapy, while OSCC patients with high Stathmin expression could not benefit from TPF induction chemotherapy. Stathmin overexpression promoted cellular proliferation and decreased OSCC cell sensitivity to TPF treatment. In addition, inhibition of the PI3K-AKT-mTOR signaling pathway decreased Stathmin expression and phosphorylation. The combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors exhibited a potent antitumor effect both in vitro and in vivo. Therefore, Stathmin can be used as a predictive biomarker for TPF induction chemotherapy and a combination therapy regimen based on Stathmin expression might improve the survival of OSCC patients.

  • Stathmin is overexpressed and regulated by mutant p53 in oral squamous cell carcinoma
    Journal of Experimental & Clinical Cancer Research, 2017
    Co-Authors: Wutong Ju, Yong Fu, Yaoyao Tu, Lizhen Wang, Zhiyuan Zhang, Laiping Zhong
    Abstract:

    The aim of this study was to investigate the oncogenic function and regulatory mechanism of Stathmin in oral squamous cell carcinoma (OSCC). Two-dimensional electrophoresis and liquid chromatography-tandem mass chromatography were applied to screen differentiated proteins during carcinogenesis in OSCC. Cell Counting Kit-8 (CCK-8) assays, colony formation, migration, flow cytometry, immunofluorescence and a xenograft model were used to detect the function of Stathmin. The correlation between Stathmin and p53 expression was analyzed using immunohistochemistry. Mutant/wild type p53 plasmids and small interfering RNA were used to examine the regulation of Stathmin. Chromatin immunoprecipitation assays and luciferase assays were performed to detect the transcriptional activation of Stathmin by p53. Overexpression of Stathmin was screened and confirmed in OSCC patients and cell lines. Silencing expression of Stathmin inhibited proliferation, colony formation and migration and promoted apoptosis. Poly ADP ribose polymerase (PARP) and cyclin-dependent kinase 1 (cdc2) were activated after silencing the expression of Stathmin. Suppression of tumorigenicity was also confirmed in vivo. Mutant p53 transcriptionally activated the expression of Stathmin in HN6 and HN13 cancer cells, but not in HN30 cells harboring wild type p53. These results suggest that Stathmin acts as an oncogene and is transcriptionally regulated by mutant p53, but not by wild-type p53. Stathmin could be a potential anti-tumor therapeutic target in OSCC.

William N Hait - One of the best experts on this subject based on the ideXlab platform.

  • reversal of Stathmin mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells
    Molecular Pharmacology, 2007
    Co-Authors: Elizabeth Alli, Jinming Yang, James M Ford, William N Hait
    Abstract:

    Antimicrotubule agents are commonly used chemotherapy drugs for the treatment of breast and other cancers. However, these agents have variable activity partly because of microtubule regulatory proteins. Stathmin, an 18-kDa phosphoprotein that promotes microtubule depolymerization, was found to be frequently overexpressed in breast cancer. We previously identified Stathmin-mediated mechanisms of resistance to antimicrotubule agents, including altered drug binding and delayed transit from G 2 into M phase, where these agents are effective in disrupting microtubule dynamics. We hypothesized that by reversing Stathmin-mediated depolymerization of microtubules or by promoting entry into mitosis, this could increase sensitivity to antimicrotubule agents in human breast cancer cells overexpressing Stathmin. We found that targeting Stathmin or wee-1 expression with RNA interference can induce microtubule polymerization and promote G 2 /M progression, respectively, and sensitize Stathmin-overexpressing breast cancer cells to paclitaxel and vinblastine. Furthermore, targeting wee-1 led to the phosphorylation of Stathmin, which is known to attenuate its activity. Therefore, these data suggest a novel approach to improving the efficacy of certain antimicrotubule agents against breast cancer by regulating the function of Stathmin.

  • effect of Stathmin on the sensitivity to antimicrotubule drugs in human breast cancer
    Cancer Research, 2002
    Co-Authors: Elizabeth Alli, Judy Bashbabula, Jinming Yang, William N Hait
    Abstract:

    Stathmin is a p53-regulated protein known to influence microtubule dynamics. Because several chemotherapeutic agents used to treat breast cancer alter the dynamic equilibrium of tubulin polymerization, Stathmin may play an important role in determining the sensitivity to these drugs. Therefore, we evaluated the effect of Stathmin expression on the action of taxanes and Vinca alkaloids using a panel of human breast cancer cell lines. Cell lines harboring mutant p53 expressed high levels of Stathmin. Two cell lines with different levels of endogenous Stathmin expression and isogenic-paired cell lines transfected to overexpress Stathmin were used to determine whether or not Stathmin modulated the sensitivity to drugs. Overexpression of Stathmin decreased polymerization of microtubules, markedly decreased binding of paclitaxel, and increased binding of vinblastine. Stathmin overexpression decreased sensitivity to paclitaxel and, to a lesser extent, to vinblastine. In contrast, Stathmin content had no significant effect on the sensitivity to chemotherapeutic drugs that do not target microtubules. Cell lines overexpressing Stathmin were more likely to enter G2 but less likely to enter mitosis as determined by fluorescence-activated cell sorting and mitotic index. This effect was magnified when Stathmin-overexpressing cells were treated with vinblastine as measured by the detection of proteins phosphorylated in early mitosis. These data suggest that the action of antimicrotubule drugs can be affected by Stathmin in at least two ways: (a) altered drug binding; and (b) growth arrest at the G2 to M boundary. Mutant p53 breast cancers exhibiting high levels of Stathmin may be resistant to antimicrotubule agents.

George F. Atweh - One of the best experts on this subject based on the ideXlab platform.

  • Stathmin-Mediated Dysregulation of Microtubules Impairs Megakaryocyte Maturation and Platelet Production
    Blood, 2010
    Co-Authors: Camelia Iancu-rubin, Joseph Tripodi, David Gajzer, Vesna Najfeld, Ronald Hoffman, George F. Atweh
    Abstract:

    Abstract 548 Maturation of megakaryocytes (MK) consists of unique processes like polyploidization and proplatelet formation that are critical for efficient platelet production. Both processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton. MT form a complex, spherical mitotic spindle that mediates polyploidization, represent the structural scaffold for proplatelet extension and enable the transport of cytoplasmic organelles into nascent platelets. While the structural organization of the MT cytoskeleton in MK is very well described at the morphological level, the mechanisms responsible for the regulation of MT dynamics during these processes are largely unknown. Stathmin is a highly conserved MT-regulatory protein that modulates MT dynamics by promoting MT depolymerization. Previous studies suggested a potential role for Stathmin in MK polyploidization. However, these studies that were performed in chemically-induced transformed cell lines reached contradictory conclusions about the role of Stathmin in megakaryopoiesis. We addressed this controversy by utilizing a more physiologically relevant experimental model of megakaryopoiesis in which primary human MK are grown in tissue culture. First, we optimized a MK liquid culture system that allows for efficient generation of mature MK capable of producing platelets in culture. Using this system, we demonstrated that the high levels of Stathmin mRNA in proliferating MK progenitors markedly decline with maturation. We used an FIV-based lentiviral expression system to prevent this physiological downregulation of Stathmin expression and investigated the effects of sustained expression on MK maturation. The sustained expression of a constitutively active form of Stathmin in MK resulted in approximately 2-fold reduction in glycoprotein GPIb expression, 3.5-fold reduction in platelet factor 4 expression and loss of up-regulation of GATA-1 expression which is normally seen during maturation. This demonstrates that the sustained activity of Stathmin prevents the up-regulation of three different markers of MK maturation, supporting the hypothesis that physiological downregulation of Stathmin is required for proper MK differentiation. We also investigated the effects of sustained Stathmin expression on polyploidization by fluorescence in situ hybridization. These studies show that Stathmin inhibited the ability of MK to achieve high levels of polyploidy. Finally, we evaluated the effects of sustained Stathmin expression on the ability of MK to produce platelets in vitro . We found that the number of platelets derived by MK expressing sustained levels of Stathmin was reduced by approximately 50% compared to those produced by control MK. This demonstrates that sustained Stathmin expression has a negative effect on platelet production, supporting the importance of MT polymerization in this process. This is the first demonstration that alterations of expression of a MT-regulatory protein can interfere with platelet production by primary MK. In summary, these studies support the importance of MT regulation during MK maturation and suggest that the physiologic downregulation of Stathmin expression is biologically important in the processes of MK maturation and platelet production. Very high levels of Stathmin expression are frequent in hematological malignancies such as leukemias and myelodysplastic syndrome. Inefficient platelet production is one of the most important features of these malignancies where bleeding from low platelet counts is one of the most common causes of death. Our studies open new avenues of investigation into the mechanisms responsible for MK maturation that may prove relevant for pathological conditions characterized by aberrant Stathmin expression and/or function. Disclosures: No relevant conflicts of interest to declare.

  • synergistic antiangiogenic effects of Stathmin inhibition and taxol exposure
    Molecular Cancer Research, 2007
    Co-Authors: Sucharita J. Mistry, Alexander Bank, George F. Atweh
    Abstract:

    Stathmin is one of the key regulators of the microtubule cytoskeleton and the mitotic spindle in eukaryotic cells. It is expressed at high levels in a wide variety of human cancers and may provide an attractive target for cancer therapy. We had previously shown that Stathmin inhibition results in the abrogation of the malignant phenotype. The microtubule-interfering drug, taxol, has both antitumorigenic and antiangiogenic properties. We had also shown that the antitumor activities of taxol and Stathmin inhibition are synergistic. We hypothesized that taxol and Stathmin inhibition may also have synergistic antiangiogenic activities. A replication-deficient bicistronic adenoviral vector that coexpresses green fluorescent protein and an anti-Stathmin ribozyme was used to target Stathmin mRNA. Exposure of endothelial cells to anti-Stathmin adenovirus alone resulted in a dose-dependent inhibition of proliferation, migration, and differentiation into capillary-like structures. This inhibition was markedly enhanced by exposure of transduced endothelial cells to very low concentrations of taxol, which resulted in a virtually complete loss of proliferation, migration, and differentiation of endothelial cells. In contrast, exposure of nontransduced endothelial cells to taxol alone resulted in a modest inhibition of proliferation, migration, and differentiation. Our detailed analysis showed that the antiangiogenic effects of the combination of Stathmin inhibition and taxol exposure are synergistic. Our studies also showed that the mechanism of this synergistic interaction is likely to be mediated through the stabilization of microtubules. Thus, this novel combination may provide an attractive therapeutic strategy that combines a synergistic antitumor activity with a synergistic antiangiogenic activity. (Mol Cancer Res 2007;5(8):773–82)

  • Targeting Stathmin in prostate cancer
    Molecular Cancer Therapeutics, 2005
    Co-Authors: Sucharita J. Mistry, Alexander Bank, George F. Atweh
    Abstract:

    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. [Mol Cancer Ther 2005;4(12):1821–9]

  • role of Stathmin in the regulation of the mitotic spindle potential applications in cancer therapy
    Mount Sinai Journal of Medicine, 2002
    Co-Authors: Sucharita J. Mistry, George F. Atweh
    Abstract:

    Abstract 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.

  • Stathmin Inhibition Enhances Okadaic Acid-induced Mitotic Arrest A POTENTIAL ROLE FOR Stathmin IN MITOTIC EXIT
    Journal of Biological Chemistry, 2001
    Co-Authors: Sucharita J. Mistry, George F. Atweh
    Abstract:

    Abstract Stathmin is a microtubule-destabilizing phosphoprotein that plays a critical role in the regulation of mitosis. The microtubule-depolymerizing activity of Stathmin is lost upon phosphorylation in mitosis. Although the role of phosphorylation of Stathmin by p34cdc2 kinase in the assembly of the mitotic spindle is well established, the role of dephosphorylation of Stathmin in mitosis is unknown. In this study, we tested the hypothesis that dephosphorylation of Stathmin may be critically important for the depolymerization of the mitotic spindle and the exit from mitosis. We compared the effects of okadaic acid, a specific inhibitor of serine/threonine protein phosphatases, on different parameters of mitotic progression in the presence or absence of Stathmin deficiency. Because okadaic acid prevents dephosphorylation of Stathmin and results in accumulation of the inactive phosphorylated form, exposure to okadaic acid would be expected to have a more profound effect on mitosis in the presence of relative Stathmin deficiency. We found that inhibition of Stathmin expression results in increased sensitivity to the antimitotic effects of okadaic acid. This was reflected by increased growth inhibition associated with mitotic arrest. A vast majority of the Stathmin-inhibited cells were found to be arrested in late metaphase/anaphase and had severe mitotic spindle abnormalities. Exposure to okadaic acid also resulted in a bigger ratio of polymerized/unpolymerized tubulin in Stathmin-inhibited cells relative to control cells. Because the only difference between the control and the Stathmin-inhibited cells is the deficiency of Stathmin in the latter, the increased susceptibility of the Stathmin-inhibited cells to okadaic acid-induced mitotic arrest implies a role for Stathmin in the later stages of mitosis.