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Tubulin isotypes are differentially regulated with STMN1 knock-out. Tubulin isotypes for α- and β-tubulin mRNAs were measured by qRT-PCR (Methods). (A) α-tubulins and (B) β-tubulins. (C) Protein levels were measure by immunoblots of whole cell lysates from each genotype, loading control is GAPDH.
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Stathmin (STMN1) protein functions to regulate assembly of the microtubule cytoskeleton by destabilizing microtubule polymers. Stathmin over-expression has been correlated with cancer stage progression, while stathmin depletion leads to death of some cancer cell lines in culture. In contrast, stathmin-null mice are viable with minor axonopathies an...
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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 associati...
Cutaneous regeneration utilizes paracrine feedback mechanisms to fine-tune the regulation of epidermal keratinocyte proliferation and migration. However, it is unknown how fibroblast-derived hepatocyte growth factor (HGF) affects these mutually exclusive processes in distinct cell populations. We here show that HGF stimulates the expression and pho...
Author Summary
Cytokinesis is the finalizing step of the complex scenario of mitosis, leading to separation of two sister cells. The cellular mechanism of cytokinesis in eukaryotes differs at least between yeasts, plants and animals. So far, it is also not clear whether all mammalian cells follow the same mechanistic rules of cytokinesis. Here, we...
N,N'-dinitrosopiperazine (DNP) with organ specificity for nasopharyngeal epithelium, is involved in nasopharyngeal carcinoma (NPC) metastasis, though its mechanism is unclear. To reveal the pathogenesis of DNP-induced metastasis, immunoprecipitation was used to identify DNP-mediated phosphoproteins. DNP-mediated NPC cell line (6-10B) motility and i...
High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre-metastatic intramucosal neoplasm that is found almost exclusively in the fallopian tube, termed "serous tubal intra...
Citations
... STMN1 was initially identified as a cytoplasmic protein phosphorylated responding to cell signal, such as growth factors 21 . STMN1 is also a key regulator of microtubule dynamics to destabilize microtubules by binding tubulin dimers [22][23][24] . STMN1 is involved in multiple diseases to play a pivotal role in cellular processes. ...
Among all cancer types, lung cancer has already become the leading cause of cancer-related death around the world. The molecular mechanism understanding this development is still needed to be improved to treat lung cancer. Stathmin (STMN1) was initially identified as a cytoplasmic protein phosphorylated responding to cell signal and controlled cell physiological processes. The dysregulation of STMN1 is found in various kinds of tumors. However, the molecular mechanism of STMN1 regulating lung cancer is still unclear. Here, we found that STMN1 was overexpressed in lung cancer tissues and associated with worse survival rates of lung cancer patients. Inhibition of STMN1 suppressed lung cancer cell growth, migration and invasion, and promoted drug sensitivity. Moreover, PTEN loss promoted STMN1 expression via PI3K/AKT pathway. PTEN loss ameliorated the inhibition of cell growth, migration and invasion, and drug sensitivity induced by STMN1 knockdown in lung cancer. The high expression of STMN1 was negatively correlated with the low expression of PTEN in lung cancer specimens. Overall, our work demonstrated that PTEN regulated the oncogenic function of STMN1 in lung cancer.
... Polymerization plays a role in regulating tubulin. Between the N-terminus and the Cterminus is the ligation domain (Küntziger et al. 2001;Ringhoff and Cassimeris 2009). When stathmin is phosphorylated, the T2S complex disintegrates, releasing microtubule dimers and inhibiting the binding of stathmin to α/β-tubulin, and the stathmin protein depolymerizes microtubules, thereby promoting microtubule formation and elongation (Bailey et al. 2015;Silva and Cassimeris 2013;Alesi et al. 2016). ...
Posttraumatic stress disorder (PTSD) is closely related to brain structures of the memory loop such as the hippocampus, amygdala, and medial prefrontal cortex (mPFC). The fear gene stathmin plays an important role in regulating fear memory. However, whether the fear gene stathmin is related to fear memory loop anomalies caused by PTSD is unclear. A single-prolonged stress (SPS) rat model of PTSD was constructed. Wistar rats were randomly divided into 5 groups: the control group, SPS 1-day group, SPS 4-day group, SPS 7-day group, and SPS 14-day group. Then, we measured the protein and mRNA expression of stathmin, p-stathmin (Ser16, Ser25, Ser38, and Ser63), β-tubulin, and MAP-1B in the hippocampus, amygdala, and mPFC in the 5 groups by immunohistochemistry, Western blotting, and qRT-PCR. The expression of the stathmin protein in the hippocampus, mPFC, and amygdala of the rat memory loop decreased gradually in the SPS 1-day group, the SPS 4-day group, and the SPS 7-day group, in which it was the lowest, and then increased. The trend of the expression of stathmin mRNA in the three areas of the memory loop was consistent with the trend of the expression of the stathmin protein. The trend of the protein expression of p-stathmin (Ser25 and Ser38) was opposite of that of stathmin; it reached a peak on the 7th day, and then decreased in the hippocampus. The protein expression of p-stathmin (Ser63) showed the same trend in the mPFC. The protein and mRNA expression of β-tubulin and MAP-1B was consistent with that of p-stathmin; it reached a peak on the 7th day, and then decreased in the rat hippocampus, mPFC, and amygdala. Stathmin in the memory loop, especially in the hippocampus, regulates microtubule structure through its phosphorylation at Ser25 and Ser38 and thereby participates in the mediation of fear memory abnormalities in PTSD.
... A comparison of STMN1+/+ vs. STMN1-/- mouse embryonic fibroblasts identified motor proteins as the largest group of genes with altered expression profiles. Interestingly, while differential expression of 13 kinesin motor subunits was detected alteration in dynein motor subunit expression was not observed, and only 5 genes encoding dynein light or intermediate chains showed altered expression [59]. ...
... In contrast, in studies performed in vertebrate model systems the function of only one member of the stai family is altered, and genetic redundancy by the remaining stathmin-like proteins may compensate and account for the observed phenotypic differences. Indeed, it has been reported in STMN1 knockout MEFs that the expression of STMN2 is decreased and STMN4 is increased [59], while in STMN1 knockout mice, an increase in the expression of STMN3 and STMN4 is observed [64,73]. The stai protein has two known activities; a MT depolymerizing activity as well as a tubulin binding activity. ...
Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai) gene in the maintenance of axonal microtubules and regulation of axonal transport in Drosophila. The stai gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of stai function in Drosophila, which has a single stai gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the stai gene family. This has allowed us to identify an essential function for stai in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of stai mutant Drosophila, we also observe additional neurological phenotypes associated with loss of stai function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in stai deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of Drosophila mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that stai has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport.
... Transgenic IGF-1 expression in muscle resulted in an increase in muscle size, body weight, and lifespan in an SMA mouse model (Bosch-Marce et al., 2011), suggesting that IGF-1 protein could be a potential factor for use in SMA therapy. Notably , IGF-1 expression is increased in embryonic fibroblasts derived from Stmn −/− mice (Ringhoff and Cassimeris, 2009), suggesting that decreased stathmin levels may lead to improvements in SMA pathology by increasing IGF-1 protein levels. Cytoskeletal defects, such as dysregulation of actin dynamics (Bowerman et al., 2007Bowerman et al., , 2010 McWhorter et al., 2003; Nolle et al., 2011), neurofilament accumulation (Cifuentes-Diaz et al., 2002), and microtubule disturbance (Torres-Benito et al., 2011; Wen et al., 2010 ), have been observed in SMA animals and were found to correlate with SMA pathology. ...
... Interestingly, SMA-Stmn −/− mice had worse motor performance (Fig. 4), shorter mean lifespan (Fig. 3A ), and fewer beneficial effects over SMA-like mice than did SMA-Stmn +/− mice. Gene expression profiles have revealed that the expression of tubulin isotypes is altered in Stmn −/− mouse embryonic fibroblasts (Ringhoff and Cassimeris, 2009). Protein levels of a predominant neuronal tubulin, the β-III isoform, were decreased in Stmn −/− cells (Ringhoff and Cassimeris, 2009). ...
... Gene expression profiles have revealed that the expression of tubulin isotypes is altered in Stmn −/− mouse embryonic fibroblasts (Ringhoff and Cassimeris, 2009). Protein levels of a predominant neuronal tubulin, the β-III isoform, were decreased in Stmn −/− cells (Ringhoff and Cassimeris, 2009). In contrast, Stmn +/− cells showed a protein level pattern similar to that of Stmn +/+ cells (Ringhoff and Cassimeris, 2009). ...
Spinal muscular atrophy (SMA), a genetic neurodegenerative disorder, is caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene that result in SMN deficiency. SMN deficiency impairs microtubule networks in Smn-deficient cells and in SMA-like motor neuron cultures. Microtubule defects can be restored by knockdown of the stathmin gene (Stmn), which is upregulated in SMA. However, whether in vivo reduction of stathmin levels could improve the pathology of SMA has not been investigated. Here we generated SMA-like mice in a Stmn knockout (KO) background through a series of genetic crosses. Analyses of motor performance and histology showed that heterozygous StmnKO (Stmn(+/-)) but not homozygous StmnKO (Stmn(-/-)) ameliorates some SMA defects, with increased microtubule densities in sciatic axons, improved motor performance, enhanced NMJ maturation, and mitigated neuroinflammation. However, Stmn deletion does not prolong the lifespan of SMA-like mice, suggesting that stathmin dysregulation and microtubule disruption are not a cause but rather a consequence of SMA pathology. This work demonstrates that limiting the amount of stathmin in SMA-like mice is effective in reducing their neuromuscular defects, whereas induced aberrant expression of stathmin in SMA-like animals is detrimental.
... 19 The ability of stathmin to remodel microtubule networks through tubulin polymerization and its microtubule-actin associations indicates a role for stathmin in tumor cell migration and invasion. 20,21 The constitutive activation and overexpression of stathmin expression has been associated with a variety of human malignancies, including breast, lung, gastric, ovarian, cervical, prostate, urothelial, hepatocellular, and colorectal carcinomas. [22][23][24][25][26][27][28] In breast cancer cell lines, stathmin overexpression has been associated with reduced taxane sensitivity and increased resistance to taxane-based chemotherapy due to delayed entry into mitosis. ...
Microtubule-associated proteins (MAPs) endogenously regulate microtubule stability. Here, the prognostic value of stathmin, a destabilizing protein, was assessed in combination with MAP-tau, a stabilizing protein, in order to evaluate microtubule stabilization as a potential biomarker.
Stathmin and MAP-tau expression levels were measured in a breast cancer cohort (n = 651) using the tissue microarray format and quantitative immunofluorescence (AQUA) technology, then correlated with clinical and pathological characteristics and disease-free survival.
Univariate Cox proportional hazard models indicated that high stathmin expression predicts worse overall survival (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.119-1.966; P = .0061). Survival analysis showed 10-year survival of 53.1% for patients with high stathmin expression versus 67% for low expressers (log-rank, P < .003). Cox multivariate analysis showed high stathmin expression was independent of age, menopausal status, nodal status, nuclear grade, tumor size, and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression (HR = 1.19; 95% CI = 1.03-1.37; P = .01). The ratio of MAP-tau to stathmin expression showed a positive correlation to disease-free survival (HR = 0.679; 95% CI = 0.517-0.891; P = .0053) with a 10-year survival of 65.4% for patients who had a high ratio of MAP-tau to stathmin versus 52.5% 10-year survival rate for those with a low ratio (log-rank, P = .0009). Cox multivariate analysis showed the ratio of MAP-tau to stathmin was an independent predictor of overall survival (HR = 0.609; 95% CI = 0.422-0.879; P = .008).
Low stathmin and high MAP-tau are associated with increased microtubule stability and better prognosis in breast cancer. Cancer 2012. © 2012 American Cancer Society.
... Alternatively, cells differing in p53 status could be dissimilar in more general ways that subsequently impact the degree of MT stability observed after stathmin depletion. For example, a large number of gene expression changes have been noted after depletion or knockout of either stathmin or p53 (Ringhoff and Cassimeris 2009a;Sur et al. 2009). ...
... For each individual cell, a region was drawn to encompass the entire cell and 100-125 Hela cells or ~ 200-250 matched HCT116 cells were measured for each treatment group. A background intensity region outside of the cell was subtracted from each measurement and the data reported as mean intensity ± SD for 3 independent experiments (Howell et al. 1999a;Ringhoff and Cassimeris 2009a). Counts of the number of acetylated MTs extending to the cell periphery included all acetylated MTs within 10 μm of the cell edge. ...
In several cancer cell lines, depleting the microtubule (MT)-destabilizing protein stathmin/oncoprotein18 leads to a G2 cell cycle delay and apoptosis. These phenotypes are observed only in synergy with low levels of p53, but the pathway(s) activated by stathmin depletion to delay the cell cycle are unknown. We found that stathmin depletion caused greater MT stability in synergy with loss of p53, measured by the levels of acetylated α-tubulin and the rate of centrosomal MT nucleation. Nocodazole or vinblastine-induced MT depolymerization abrogated the stathmin-depletion induced G2 delay, measured by the percentage of cells staining positive for several markers (TPX2, CDK1 with inhibitory phosphorylation), indicating that MTs are required to lengthen G2. Live cell imaging showed that stathmin depletion increased time in G2 without an impact on the duration of mitosis, indicating that the longer interphase duration is not simply a consequence of a previous slowed mitosis. In contrast, stabilization of MTs with paclitaxel (8 nM) slowed mitosis without lengthening the duration of interphase, demonstrating that increased MT stability alone is not sufficient to delay cells in G2.
... Expression of TGF-β was also analyzed by Western blotting, and it was found that expression of TGF-β in response to treatment with either AS extract or FA correlated with the results of the collagen secretion assay (Figure 5(c)). The functions of STMN1, ARPC5, NDKB, and MARE1 are known to be associated with cell mobility and wound healing23242526; however, the expression levels of these proteins, as detected by our proteomic analysis, varied, and they grouped into different clusters (Figure 3, cluster C, D, E) in response to drug treatment. In these circumstances it is important to clarify the effects of each treatment on the fibroblasts, and therefore cell migration and wound healing assays were carried out on cells treated with either AS extract or FA. ...
Angelica sinensis (AS) is a traditional Chinese herbal medicine that has been formulated clinically to treat various form of skin trauma and to help wound healing. However, the mechanism by which it works remains a mystery. In this study we have established a new platform to evaluate the pharmacological effects of total AS herbal extracts as well as its major active component, ferulic acid (FA), using proteomic and biochemical analysis. Cytotoxic and proliferation-promoting concentrations of AS ethanol extracts (AS extract) and FA were tested, and then the cell extracts were subject to 2D PAGE analysis. We found 51 differentially expressed protein spots, and these were identified by mass spectrometry. Furthermore, biomolecular assays, involving collagen secretion, migration, and ROS measurements, gave results that are consistent with the proteomic analysis. In this work, we have demonstrated a whole range of pharmacological effects associated with Angelica sinensis that might be beneficial when developing a wound healing pharmaceutical formulation for the herbal medicine.
... Another possibility is that the phenotype of knockout mice is somehow compensated by changes in the expression of other factors involved in the control of microtubule dynamics, cell motility and/ or cell cycle control thus allowing the development of a normal organism. Indeed, published [137] and our unpublished observations demonstrate that cells knockout for stathmin display profound alteration in gene expression. It is also important to consider that in vivo phenotype of transient versus stable gene knock out is often profoundly different, suggesting that many levels of molecular compensation occur during the development of knockout mice. ...
Introduction:
Stathmin is a microtubule-destabilizing phosphoprotein, firstly identified as the downstream target of many signal transduction pathways. Several studies then indicated that stathmin is overexpressed in many types of human malignancies, thus deserving the name of Oncoprotein 18 (Op18). At molecular level, stathmin depolymerizes microtubules by either sequestering free tubulin dimers or directly inducing microtubule-catastrophe. A crucial role for stathmin in the control of mitosis has been proposed, since both its overexpression and its downregulation induce failure in the correct completion of cell division. Accordingly, stathmin is an important target of the main regulator of M phase, cyclin-dependent kinase 1.
Areas covered:
Recent evidences support a role for stathmin in the regulation of cell growth and motility, both in vitro and in vivo, and indicate its involvement in advanced, invasive and metastatic cancer more than in primary tumors.
Expert opinion:
Many studies suggest that high stathmin expression levels in cancer negatively influence the response to microtubule-targeting drugs. These notions together with the fact that stathmin is expressed at very low levels in most adult tissues strongly support the use of stathmin as marker of prognosis and as target for novel anti-tumoral and anti-metastatic therapies.
... The choice of KEGG spider in the current work is because it takes into account the density of the metabolic networks for estimating the statistical significance of the model quality (Antonov et al., 2008). KEGG spider has been used to reveal changes in the network of genes contributing to cell motility in mouse embryo fibroblast lacking stathmin, a microtubule regulatory protein (Ringhoff and Cassimeris, 2009). ...
