Abstract
Septins are a novel family of GTP-binding proteins which are essential for cytokinesis,
vesicle trafficking, cytoskeletal reorganization and membrane dynamics. They are abundantly
expressed in many mitotic cells. Interestingly, they are also expressed in non-dividing
cells such as neurons and platelets in which they play an important role in exocytosis.
Platelets from SEPT5 knockout mice show an enhanced serotonin secretion and platelet
aggregation in response to subthreshold levels of agonists. Septins are associated
with a wide array of critical biological events such as neoplasia, neurodegenerative
diseases, infections and exocytosis. The role of septins in oncogenesis is complex.
Increased expression of some septins seems to trigger the growth of tumor cells. However,
other septin isoforms are shown to promote apoptosis and function as tumor suppressor
proteins. Interestingly, septins form complexes consisting of multiple septin polypeptides
and assemble into filaments and ring-like, higher-order structures. The different
septins and their various isoforms seem to determine the function of the septin complex.
Zusammenfassung
Septine bilden eine neue Familie GTP-bindender Proteine, die für Zytokinese, intrazellulären
Vesikeltransport, Organisation des Zytoskeletts und Membranveränderungen essentiell
sind. Sie werden in vielen sich schnell-teilenden Zellen wie auch in sich nicht-teilenden
Zellen exprimiert und sind hier für die Exozytose wichtig. Septine sind in vielfältige
wichtige zellbiologische Prozesse involviert wie z.B. Onkogenese, neurodegenerative
Erkrankungen, Infektionen und Exozytose. Die Rolle der Septine in der Onkogenese ist
komplex. Erhöhte Expression einiger Septine scheint das Tumorwachstum zu triggern.
Jedoch fördern andere Septin-Isoformen die Apoptose und funktionieren als Tumorsuppressor-Proteine.
Interessant ist, dass Septine Komplexe bilden, die aus mehreren Septinproteinen bestehen
und die dann wiederum Filamente oder ringähnliche Strukturen bilden. Die unterschiedlichen
Septine und ihre Isoformen scheinen die Funktion der verschiedenen Septinkomplexe
zu bestimmen.
Key words
septins - GTP-binding proteins - hemostasis - platelets - neuropathology - oncogenesis
Schlüsselwörter
Septine - GTP-bindende Proteine - Hämostase - Thrombozyten - Neuropathologie - Onkogenese
References
1
Amir S. et al .
MSF-A interacts with hypoxia-inducible facto transcriptional activation to affect
tumorigenicity and angiogenesis.
Cancer Res.
2006;
66
856-866
2
Beites CL. et al .
The septin CDCrel-1 binds syntaxin and inhibits exocytosis.
Nat. Neurosci.
1999;
2
434-439
3
Beites CL. et al .
Expression and analysis of properties of septin CDCrel-1 in exocytosis.
Methods Enzymol.
2001;
329
499-510
4
Bläser S. et al .
Human septin-septin interaction: CDCrel-1 partners with KIAA0202.
FEBS Letters.
2002;
519
169-172
5
Bläser S. et al .
Isolation of new isoforms, characterization and expression analysis of the human septin
SEPT8 (KIAA0202).
Gene.
2003;
312
313-320
6
Bläser S. et al .
The novel human platelet septin SEPT8 is an interaction partner of SEPT4.
Thromb Haemost.
2004;
91
959-966
7
Bläser S. et al .
Human endothelial cell septins: SEPT11 is an interaction partner of SEPT5.
J Pathol.
2006;
210
103-110
8
Budarf ML. et al .
Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/Velo-cardio-facial
chromosomal region 22q11.2.
Hum Med Genet.
1995;
4
763-766
9
Cheon MS. et al .
Expression profiles of proteins in fetal brain with Down syndrome.
J Neural Transm.
2001;
61
((Suppl))
311-319
10
Choi P. et al .
SEPT5_v2 is a parkin-binding protein.
Brain Res Mol Brain Res.
2003;
117
179-189
11
Dent J. et al .
A prototypic platelet septin and its participation in secretion.
Proc Nat Acad Sci.
2002;
99
3064-3069
12
Dong Z. et al .
Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression
of the parkin target protein, CDCrel-1.
Proc Natl Acad Sci USA.
2003;
100
12438-12443
13
Elhasid R. et al .
Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic
leukemia patients.
Oncogene.
2004;
23
5468-5475
14
Engidawork E. et al .
Aberrant protein expression in cerebral cortex of fetus with Down syndrome.
Neuroscience.
2003;
122
145-154
15
Field CM. et al .
A purified Drosophila septin complex forms filaments and exhibits GTPase activity.
J Cell Biol.
1996;
133
605-616
16
Field CM. et al .
Septins: cytoskeletal polymers or signalling GTPases?.
Trends Cell Biol.
1999;
9
387-394
17
Flaumenhaft R. et al .
Proteins of the exocytic core complex mediate platelet alpha-granule secretion. Roles
of vesicle-associated membrane protein, SNAP-23 and syntaxin 4.
J Biol Chem.
1999;
274
2492-2501
18
Frazier JA. et al .
Polymerization of purified yeast septins: evidence that organized filament arrays
may not be required for septin function.
J Cell Biol.
1998;
143
737-749
19
Funke B. et al .
Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge
syndrome have middle and inner ear defects.
Hum Mol Genet.
2001;
10
2549-2556
20
Garcia-Fernandez M. et al .
Role of the Sept4 gene in stem cell apoptosis and tumor suppression.
EMBO Workshop on the Biology & Biochemistry of Septins & Septin Function, Monte Verita,
Switzerland.
2007;
21
Gottfried Y. et al .
The pro-apoptotic ARTS/Sept4 protein is significantly reduced in post-mortem brains
from schizophrenic patients.
Schizophr Res.
2007;
96
257-266
22
Hartwell LH. et al .
Genetic control of the cell division cycles in yeast.
Science (Wash DC).
1974;
183
46-51
23
Hsu SC. et al .
Subunit composition, protein interactions, and structures of the mammalian brain sec6/8
complex and septin filaments.
Neuron.
1998;
20
1111-1122
24
Ihara M. et al .
Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmatic inclusions
found in Parkinson's disease and other synucleinopathies.
J Biol Chem.
2003;
278
24095-24102
25
Ihara M. et al .
Cortical organization by the septin cytoskeleton is essential for structural and mechanical
integrity of mammalian spermatozoa.
Dev Cell.
2005;
8
343-352
26
Ihara M. et al .
Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression
of alpha-synuclein neurotoxicity.
Neuron.
2007;
53
519-533
27
Kato K. et al .
Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype
with increased α-granule size.
Blood.
2004;
104
2339-2344
28
Kinoshita M. et al .
Nedd5, a mammalian septin, is a novel cytoskeletal component interacting with actin-based
structures.
Genes Dev.
1997;
11
1535-1547
29
Kinoshita A. et al .
Identification of septins in neurofibrillary tangles in Alzheimer′s disease.
Am J Pathol.
1998;
153
1551-1560
30
Kinoshita M. et al .
Roles of septins in the mammalian cytokinesis machinery.
Cell Struct Funct.
2001;
26
667-670
31
Kinoshita M.
Assembly of mammalian septins.
J Biochem.
2003;
134
491-496
32
Kuhlenbäumer G. et al .
Mutations in SEPT9 cause hereditary neuralgic amyotrophy.
Nat Genet.
2005;
37
1044-1046
33
Larisch S.
The ARTS connection: role of ARTS in apoptosis and cancer.
Cell cycle.
2004;
3
1021-1023
34
Lopez JA. et al .
Cloning of the alpha chain of human platelet glycoprotein Ib: A transmembrane protein
with homology to leucine-rich alpha2-glycoprotein.
Proc Natl Acad Sci USA.
1987;
84
5615-5619
35
Macara IG. et al .
Mammalian septins nomenclature.
Mol Biol Cell.
2002;
13
4111-4113
36
Martinez C. et al .
Platelet septin complexes form rings and associate with the microtubular network.
J Thromb Haemost.
2006;
4
1388-1395
37
Reed GL. et al .
Molecular mechanisms of platelet exocytosis: insights into the “secrete” life of thrombocytes.
Blood.
2000;
96
3334-3342
38 Ruggeri ZM. The platelet glycoprotein Ib-IX complex. In: BS Coller, ed.
Progress in Hemostasis and Thrombosis . WB Saunders Company, Philadelphia 1991: 35-68
39
Russell SE. et al .
Do septins have a role in cancer?.
Br J Cancer.
2005;
93
499-503
40
Sheets MD. et al .
Point mutations in AAUAAA and poly (A) addition site: effects on the accuracy and
efficiency of cleavage and polyadenylation in vitro.
Nucleic Acids Res.
1990;
18
5799-5805
41
Sheffield PJ. et al .
Borg/septin interactions and the assembly of mammalian septin heterodimers, trimers,
and filaments.
J Biol Chem.
2003;
278
3483-3488
42
Sirajuddin M. et al .
Structural insight into filament formation by mammalian septins.
Nature.
2007;
449
311-315
43
Slater DJ. et al .
MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant
acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and
MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase
II cleavage site.
Oncogene.
2002;
21
4706-4714
44
Son JH. et al .
Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic
neurons.
J Neurochemistry.
2005;
94
1040-1053
45
Sorensen AB. et al .
Analysis of Sept9 mutant mice.
EMBO Workshop on the Biology & Biochemistry of Septins & Septin Function, Monte Verita,
Switzerland.
2007;
46
Takehashi M. et al .
Septin 3 gene polymorphism in Alzheimer's disease.
Gene Expr.
2004;
11
263-270
47
Tanaka M. et al .
Characterization of tissue- and cell-type-specific expression of a novel human septin
family gene, Bradeion.
Biochem Biophys Res Commun.
2001;
286
547-553
48
Tanaka M. et al .
Impaired expression of a human septin family gene Bradeion inhibits the growth and
tumorigenesis of colorectal cancer in vitro and in vivo.
Cancer Gene Ther.
2002;
9
483-488
49
Trimble WS.
Septins: a highly conserved family of membrane-associated GTPases with functions in
cell division and beyond.
J Membr Biol.
1999;
169
75-81
50
Versele M. et al .
Some assembly required: yeast septins provide the instruction manual.
Trends Cell Biol.
2005;
15
414-424
51
Weirich CS. et al .
The septin family of GTPases: architecture and dynamics.
Nat Rev Mol Cell Biol.
2008;
9
478-489
52
Xie Y. et al .
The GTP-binding protein septin 7 is critical for dendrite branching and dendritic-spine
morphology.
Current Biol.
2007;
17
1746-1751
53
Yagi M. et al .
Structural characterization and chromosomal location of the gene encoding human platelet
glycoprotein Ibβ.
J Biol Chem.
1994;
269
17424-17427
54
Zhang J. et al .
Phosphatidylinositol polyphosphate binding to the mammalian septin H5 is modulated
by GTP.
Curr Biol.
1999;
9
1458-1467
55
Zhang Y. et al .
Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation
of the synaptic vesicle-associated protein, CDCrel-1.
Proc Natl Acad Sci USA.
2000;
97
13354-13359
56
Zieger B. et al .
Alternative expression of platelet glycoprotein Ibβ mRNA from an adjacent 5′ gene
with an imperfect polyadenylation signal sequence.
J Clin Invest.
1997;
99
520-525
57
Zieger B. et al .
Characterization and expression analysis of two human septin genes, PNUTL1 and PNUTL2.
Gene.
2000;
261
197-203
58
Fischer M. et al .
Risk estimation of neuroblastoma patients using molecular markers.
Klin Padiatr..
2008;
220
137-146
59
Faber J. et al .
Defining leukemia stem cells in MLL-translocated leukemias: implications for novel
therapeutic strategies.
Klin Padiatr..
2007;
219
306-311
Correspondence
Dr. K. Sandrock
University Hospital Freiburg
Department of Pediatrics and Adolescent Medicine
Mathildenstr.1
79106 Freiburg i. Br.
Germany
Telefon: +49/761/270 71 93
Fax: +49/761/270 45 82
eMail: kirstin.sandrock@uniklinik-freiburg.de