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STATHMIN 1; STMN1

STATHMIN 1; STMN1

Alternative titles; symbolsSTATHMIN; SMNLEUKEMIA-ASSOCIATED PHOSPHOPROTEIN p18; LAP18METABLASTINOP18HGNC Approved Gene Symbol: STMN1Cytogenetic location: 1p36.11...

Alternative titles; symbols

  • STATHMIN; SMN
  • LEUKEMIA-ASSOCIATED PHOSPHOPROTEIN p18; LAP18
  • METABLASTIN
  • OP18

HGNC Approved Gene Symbol: STMN1

Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:25,884,178-25,906,879 (from NCBI)

▼ Description
Members of the stathmin family sequester tubulin (see 191130) in a ternary complex, with 2 tubulins for every stathmin-like protein. Formation of the complex interferes with microtubule dynamics in vitro and in vivo.

▼ Cloning and Expression
Hanash et al. (1988) demonstrated an increased level of an 18-kD cytosolic phosphoprotein (p18) in the cells of various types of human acute leukemia. The cDNA that encodes p18 was cloned by Zhu et al. (1989).

Sobel et al. (1989) suggested that this protein be called stathmin, from the Greek 'stathmos' (relay).

By immunofluorescence microscopy, Gavet et al. (1998) detected endogenous HeLa cell stathmin expressed in a punctate cytoplasmic distribution, with staining concentrated around the nucleus.

By real-time quantitative RT-PCR, Bieche et al. (2003) detected stathmin expression in all tissues examined. Expression was strongest in fetal and adult brain, spinal cord, and cerebellum, followed by thymus, bone marrow, testis, and fetal liver. Expression was intermediate in colon, ovary, placenta, uterus, and trachea, and was readily detected at substantially lower levels in all other tissues examined. Lowest expression was found in adult liver.

▼ Gene Function
Sobel (1991) stated that stathmin is a ubiquitous, phylogenetically conserved protein present in the cytoplasm in a variety of unphosphorylated and phosphorylated forms. Its expression and phosphorylation are regulated throughout development in response to extracellular signals regulating cell proliferation, differentiation, and function. The overall pattern of its molecular forms reflects the activation of corresponding second messenger pathways. This phosphoprotein is therefore a good candidate for a general relay in signal transduction, possibly integrating diverse signals from the cell's environment.

Kumar and Haugen (1994) observed that stathmin exists in bone cells and proposed that the protein may play a role in altering osteoblast growth and response to various hormonal stimuli.

Maucuer et al. (1995) identified 4 mouse proteins that could interact with human stathmin in a yeast 2-hybrid screen of an embryonic mouse expression library. These included a member of the heat-shock protein family (Bip; 138120), retinoblastoma-inducible coiled-coil protein (Rb1cc1; 606837), a putative serine/threonine kinase, and a second protein with a coiled-coil structure.

Using antibody directed against stathmin phosphorylated on ser16, Gavet et al. (1998) found that interphase HeLa cells were weakly stained, but mitotic cells were strongly labeled. Staining of mitotic cells increased from prophase to metaphase and decreased at cytokinesis. Analysis of synchronized cell extracts showed that phosphorylation of ser16 was detected in G2/M phases of the cell cycle. Overexpression of several phosphorylation site mutants suggested that stathmin induces depolymerization of interphase and mitotic microtubules in its unphosphorylated state, but is inactivated by phosphorylation in mitosis.

Wen et al. (2010) described a potential link between stathmin and microtubule defects in spinal muscular atrophy (SMA; 253300), a motor neuron degeneration disorder caused by defects in the survival of motor neuron-1 gene (SMN1; 600354) that result in insufficient SMN protein. Stathmin was identified by proteomics analysis of Smn-knockdown NSC34 cells. Stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta-3-tubulin (TUBB3; 602661) levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth, and reduced the defect in mitochondria transport in SMA-like motor neurons. The authors concluded that aberrant stathmin levels may play a detrimental role in SMA.

By screening human brain tumor transcript library supernatants with human astrocytes to identify proteins interacting with TLR3 (603029), Bsibsi et al. (2010) identified STMN1. Wildtype mouse astrocytes, but not astrocytes from Tlr3-deficient mice, responded to Stmn1. STMN1 and poly(I:C) induced the same set of transcripts in human astrocytes. STMN1 also activated intracellular TLR3 in human microglia. The STMN1 TLR3 agonist activity was dependent on an intact alpha-helical structure of STMN1. TLR3-transfected human embryonic kidney cells failed to respond to STMN1, suggesting a requirement for additional surface factors present on astrocytes and microglia. Confocal microscopy of multiple sclerosis (see 126200) lesions demonstrated colocalization of STMN1 and TLR3 in inflamed areas, primarily in astrocytes and microglia, but only occasionally in oligodendrocytes.

▼ Mapping
Ferrari et al. (1990) mapped the LAP18 gene to 1p36.1-p35 by Southern analysis of human-rodent somatic cell hybrid DNAs and by chromosome in situ hybridization using a p18 genomic probe. They pointed out that this region of chromosome 1 is frequently involved in visible deletions or loss of heterozygosity in tumors derived from neural crest cells, particularly neuroblastomas and melanomas. The high levels of expression of p18 in brain and neuroendocrine tumor cells, its possible role in growth regulation, and its chromosomal location suggest that this gene may be involved in genetic events underlying some of these tumors.

Mock et al. (1993) mapped the homologous gene to distal mouse chromosome 4 by haplotype analysis of progeny from an interspecific backcross. Okazaki et al. (1993) showed that the stathmin gene in mouse is about 6 kb long and is located on chromosome 4 with possible pseudogenes on chromosomes 9 and 17. The related gene SCG10 (600621) was mapped to mouse chromosome 3.

▼ Animal Model
Shumyatsky et al. (2005) found that stathmin was highly expressed in the lateral nucleus of the amygdala, as well as in the thalamic and cortical structures that send information to the amygdala about conditioned and unconditioned stimuli. Stathmin-knockout mice exhibited decreased memory in amygdala-dependent fear conditioning and failed to recognize danger in innately aversive environments. In contrast, these mice did not show deficits in the water maze, a spatial task dependent on the hippocampus, where stathmin is not normally expressed. The amygdala of knockout mice showed increased amounts of microtubules, although neuronal morphology and synaptic transmission was normal. However, whole-cell recordings from amygdala slices isolated from stathmin-knockout mice showed deficits in spike-timing-dependent long-term potentiation (LTP). The findings suggested that stathmin is required for the induction of LTP in afferent inputs to the amygdala and is essential in regulating both innate and learned fear. Shumyatsky et al. (2005) postulated that a decrease in microtubule dynamics could result in deficits in synaptic plasticity.

Martel et al. (2008) observed that stathmin-null female mice showed improper threat assessment, which affected innate parental care. They showed a profound deficiency in maternal behavior, including lack of motivation for retrieving pups and inability to choose a safe location for nest building. In addition, stathmin-null adult females showed increased social interactions as hosts in the host-intruder paradigm. RNA studies detected stathmin expression in the basolateral amygdala (BLA). Bilateral lesions in the BLA of wildtype females resulted in similar deficits in pup retrieval. The findings implicated stathmin as a critical molecular component linking neural circuitry of the BLA nuclei with innate behavior resulting from threat assessment.

Tags: 1p36.11