Disease relevance of STMN1

• PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells [1].
• Stathmin, a probable relay protein possibly integrating multiple intracellular regulatory signals [reviewed in Sobel (1991) Trends Biochem. Sci. 16, 301-305], was expressed in Escherichia coli at levels as high as 20% of total bacterial protein [2].
• Overexpression of stathmin in oral squamous-cell carcinoma: correlation with tumour progression and poor prognosis [3].
• When messenger ribonuleic acid from human osteosarcoma (Saos-2) cells treated with 10(-8)M 1,25-dihydroxyvitamin D3 was compared with that of cells treated with vehicle alone by this method, we observed an increase in the intensity of a band that on subsequent DNA sequence analysis was found to encode stathmin [4].
• Decreased protein levels of stathmin in adult brains with Down syndrome and Alzheimer's disease [5].

Psychiatry related information on STMN1

• Patients versus controls showed significantly: lower Lag Phase and Vitamin E (Vit E) concentrations in plasma and low-density lipoproteins (LDL), higher LDL thiobarbituric acid reactive substances (TBARS), higher fatigue and lower muscle pain thresholds to electrical stimulation [6].
• Effects of a Lag 1 reinforcement schedule on appropriate and varied responding to the social question, "What do you like to do?" and effects of the proportion of preferred stimuli present during training on the amount of varied responding in each session were investigated with students with autism [7].

High impact information on STMN1

• Regulation of Op18/stathmin by phosphorylation continues to capture much attention [8].
• The oncoprotein 18/stathmin family of microtubule destabilizers [8].
• We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin [9].
• 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 [10].
• 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 [10].

Chemical compound and disease context of STMN1

• In malignant T lymphoma cells, dephosphorylation and nuclear translocation of pp19/cofilin occur spontaneously through constitutive activation of a serine phosphatase [11].
• Treatment of the neuroblastoma cell line SMS-KCNR, which contains 75 copies of the N-myc gene, with retinoic acid for ten days resulted in an increase in Op18 phosphorylation [12].
• In this study we analyzed the level of unphosphorylated Op18 and of its major phosphorylated forms, Op18a and Op18b, in a series of 177 childhood acute leukemias by means of quantitative two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) [13].
• Persistent growth of BALB/C mouse plasmacytoma and human myeloma cell lines in the presence of phorbol myristate acetate is associated with continued expression of Lap18 (stathmin) [14].

Biological context of STMN1

• Stathmin is a ubiquitous cytosolic phosphoprotein participating in the relay and integration of diverse intracellular signaling pathways involved in the control of cell proliferation, differentiation, and activities [15].
• Our results suggest that the interaction of stathmin with Hsc70 is specific in both proteins and most likely biologically relevant in the context of their functional implication in the control of numerous intracellular signaling and regulatory pathways, and hence of normal cell growth and differentiation [15].
• Cell-cycle-regulated phosphorylation of oncoprotein 18 on Ser16, Ser25 and Ser38 [16].
• Moreover, during mitosis, a burst of phosphorylation was observed and at this stage of the cell cycle a major fraction of Op18 was phosphorylated at multiple sites [16].
• Phosphorylation of Op18 during mitosis was located primarily on Ser38 and to lesser extent on Ser25, Ser16 and at an unidentified C-terminal residue [16].

Anatomical context of STMN1

• Altogether, our results demonstrate in vivo the functional conservation of the stathmin domain within each protein of the stathmin family, with a microtubule destabilizing activity most likely essential for their specific biological function(s) [17].
• We have identified two serine residues of Op18 that are phosphorylated after triggering by the T cell antigen receptor [16].
• Treatment of K562 leukemia cell line with hemin that induces terminal differentiation resulted in decreased expression of Op18 [18].
• The oncoprotein 18 (Op18) gene encodes a proliferation-related cytosolic phosphoprotein, which is induced in normal lymphocytes following mitogenic stimulation [18].
• Effects of quercetin on heat-induced phosphorylation of stathmin in JURKAT cells were examined [19].

Associations of STMN1 with chemical compounds

• Transient expression of each of the neural phosphoproteins of the stathmin family showed that they are at least partially associated to the Golgi apparatus and not to other major membrane compartments, probably through their different NH2-terminal domains, as described for SCG10 [17].
• We have recently identified two distinct proline-directed kinase families that phosphorylates Op18 with overlapping but distinct site preference [20].
• We also demonstrate that Ser-16 of Op18 is specifically phosphorylated in response to the Ca2+ signal generated by CD3 stimulation or by the Ca2+ ionophore ionomycin [20].
• Immunoblot analysis of phosphorylated stathmin showed that heat-induced phosphorylation at Ser-38 was inhibited by quercetin but not by staurosporine [19].
• This result strongly suggests that glutamic acid in position 25 is able to mimic the putative interactions of phosphoserine-25 with phosphoserine-16, as well as the resulting conformational changes that are probably also related to the functional regulation of stathmin [2].
• Loss of stathmin expression increased responsiveness of tumor cells to the treatment with cytostatic drugs targeting MT-stability (paclitaxel, vinblastine) and to DNA cross-linking agents (cisplatin) [21].

Physical interactions of STMN1

• Hsc70 is among the proteins coimmunoprecipitated with stathmin, and it is the main protein retained specifically on stathmin-Sepharose beads identified by one- and two-dimensional electrophoresis and immunoblots [15].
• Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16 [22].
• The aim of this study was to probe the native structure of stathmin and to delineate its minimal region able to interact with tubulin [23].
• We further demonstrate that DOCK7 and Rac activation lead to phosphorylation and inactivation of the microtubule destabilizing protein stathmin/Op18 in the nascent axon and that this event is important for axon development [24].
• We further identified two PPIL1-interacting proteins, SNW1/SKIP (SKI-binding protein) and stathmin [25].

Enzymatic interactions of STMN1

• In transient expression studies, we found that in addition to different stimuli osmotic stress activates p38 delta to phosphorylate stathmin [26].
• These results strongly suggest that heat stress activates Cdk-1 which phosphorylates Ser 37 on the stathmin molecule [27].

Regulatory relationships of STMN1

• Bovine serum albumin (BSA)-Sepharose did not bind Hsc70, and anti-stathmin antisera specifically inhibited the interaction of Hsc70 with stathmin-Sepharose [15].
• The Rac Activator DOCK7 Regulates Neuronal Polarity through Local Phosphorylation of Stathmin/Op18 [24].
• 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 [28].
• Stathmin phosphorylation is regulated in striatal neurons by vasoactive intestinal peptide and monoamines via multiple intracellular pathways [29].
• 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 [30].

Other interactions of STMN1

• These findings raised the possibility that Op18 may be a substrate for both receptor-regulated calcium-induced protein kinases and the MAP kinase family, as well as being a substrate for the cell-cycle-regulated cdc2 kinase family [16].
• These findings suggest that Op18 may be a physiological substrate for several members of the cdc2 kinase family during both the S-phase and the mitotic phase of the cell cycle [16].
• In vivo, the transient expression of neural phosphoproteins of the stathmin family leads to their localization at Golgi membranes and, as previously described for stathmin and SCG10, to the depolymerization of interphasic microtubules [31].
• 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 [32].
• Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase [33].

Analytical, diagnostic and therapeutic context of STMN1

• Control of microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis [34].
• We have identified a rapid protein phosphorylation event at residue serine 16 of stathmin using two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption/ionization mass spectrometry in combination with post-source decay analysis, which is induced by the epidermal growth factor receptor [22].
• Proteolytic fragments of p19 and pp19 were examined by liquid chromatography/mass spectrometry (LC/MS) [35].
• Probing the native structure of stathmin and its interaction domains with tubulin. Combined use of limited proteolysis, size exclusion chromatography, and mass spectrometry [23].
• The proposed pH-sensitive dual function of stathmin was further evaluated by circular dichroism spectroscopy and nuclear magnetic resonance [36].

References