Survivin

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Survivin
Survivin

Existing structural data: s. UniProt

Properties of human protein
Mass / length primary structure 142 amino acids
Secondary to quaternary structure Homodimer
Isoforms 7th
Identifier
Gene name BIRC5
External IDs
Inhibitor classification
MEROPS I32.005

Survivin , also known as BIRC5 or API4 , is an apoptosis-inhibiting protein that is essentially only produced by cancer cells . The tumor antigen is also called "survival protein". This is where the English name - to survive - derives .

Since survivin is essentially only found in malignancies and not in normal tissue in the adult body and it is of great importance for the regulation of apoptosis in transformed cells, it was soon after its discovery as a potential biomarker for the diagnosis and prognosis of cancer, as well as proposed a possible target in cancer therapy .

discovery

Survivin was first identified in 1997 by G. Ambrosini, C. Adida, and DC Altieri in various malignant cell lines and a number of fetal tissues. It was discovered by hybridization screening of a human gene bank with the cDNA of the factor Xa receptor EPR-1 ( effector cell protease receptor-1 ).

Occurrence

During embryonic development , Survivin's function is to monitor the correct transmission of chromosomes in the dividing cells . After embryonic development, this protein is hardly present in resting healthy cells. In contrast, the cells of almost all tumors produce survivin in order to grow in an uncontrolled manner and to be able to better protect themselves against therapies.

properties

The gene responsible for the expression of survivin is 14.7 kb in size and is located on chromosome 17q25 . It consists of three introns and four exons . The gene codes for the protein, which consists of 142 amino acids and has a molar mass of 16,390  Da . As a class 3 IAP ( inhibitor of apoptosis ), Survivin prevents the apoptotic function of essential BIR domains ( baculovirus IAP repeats ).

There are currently five known splice variants of Survivin:

  • wt survivin (142 amino acids)
  • 2B survivin (165 amino acids)
  • Survivin-Δ3 (137 amino acids)
  • 3B survivin (discovered in 2005).
  • 2α-survivin (74 amino acids)

Survivin differs from other IAPs in:

  • the presence of only one BIR domain
  • the lack of a CARD ( caspase recruitment domain )
  • the lack of a RING domain ( really interesting new gene )
  • the low molar mass of 16.5 kDa.

The survivin protein is a bow-tie-shaped dimer. A survivin monomer consists of a BIR domain, the three α-helices and a three-stranded β-sheet . For the most part, the shape of the domain is stabilized by a zinc finger (with four zinc ligands). The dimer formation is formed by hydrogen bonds and van der Waals forces .

The amino acid sequence for survivin (species: Homo sapiens ) in one letter code is: 

mgaptlppaw qpflkdhris tfknwpfleg cactpermae agfihcpten epdlaqcffc
fkelegwepd ddpieehkkh ssgcaflsvk kqfeeltlge flkldrerak nkiaketnnk
kkefeetakk vrraieqlaa md

Working mechanism

The mechanisms of survivin's anti-apoptotic function have not yet been fully explored. Survivin is supposed to antagonize the mitochondria-dependent, so-called intrinsic apoptosis pathway. The inhibiting effect of survivin on the apoptosis cascade appears to be mediated by inactivation of the cell death protease caspase -9 and to be dependent on a cofactor (HBXIP). The complete elucidation of the functional mechanism of Survivin would be of great interest, especially for possible therapeutic approaches in cancer diseases.

Diagnostic applications

Survivin can be detected in the urine of bladder cancer. Some clinical studies are currently ongoing.

Further diagnostic applications are under development.

Potential therapeutic approaches in oncology

All cytotoxic chemotherapeutic agents - like radiation therapy - work by inducing apoptosis in malignant cells. The increased expression of apoptosis inhibitors is a countermeasure used by cancer cells to ensure their survival. Accordingly, the overexpression of survivin in cancer cells is associated with a significantly reduced survival rate of the affected patients, a higher likelihood of recurrence and a reduced apoptosis rate in tumor cells. Survivin is therefore an important target molecule for the development of new therapeutic drugs.

After its production, the survivin is transported into the cytoplasm , which presumably plays an important role in the cancer-promoting function of survivin. In some patients this transport is obviously disturbed and the survivin is mainly in the cell nucleus . Initial studies show that these patients have a better chance of survival.

This mechanism is the starting point for new cancer therapies designed to prevent survivin from being transported into the cytoplasm. The aim is to make tumor cells more sensitive to conventional cancer therapies ( chemotherapy and radiation therapy ). The company Lilly has an antisense - oligonucleotide in the development, which is to block survivin.

YM155 of Astellase is a survivin suppressor , designed to target the expression is intended to suppress survivin. The compound is a small molecule with a naphthoquinone base and is in clinical trials (phase II (as of September 2009), for non-small-cell lung cancer NSCLC and malignant melanoma ).

Even cancer immunotherapeutic approaches using survivin are in development. What all these concepts have in common is that, as a complementary therapy, they are intended to potentiate the effectiveness of conventional therapeutic interventions (chemotherapy and radiation therapy).

Others

Resveratrol , a polyphenol found in red wine , for example , is apparently able to inhibit survivin.

literature

  • RK Kanwar, CH Cheung, JY Chang, JR Kanwar: Recent advances in anti-survivin treatments for cancer. In: Current Medicinal Chemistry Volume 17, Number 15, 2010, pp. 1509-1515, PMID 20166933 . (Review).
  • M. Guha and DC Altieri: Survivin as a global target of intrinsic tumor suppression networks. In: Cell Cycle 8, 2009, pp. 2708-2710, PMID 19717980 (review).
  • DC Altieri: New Wirings in the Survivin Networks. In: Oncogene 27, 2008, pp. 6276-6284, PMID 18931693 (review), PMC 2683067 (free full text).
  • AC Mita et al. a .: Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. In: Clin Cancer Res 14, 2008, pp. 5000-5005, PMID 18698017 , doi: 10.1158 / 1078-0432.CCR-08-0746 (review).
  • H. Yamamoto et al. a .: Cancer cells survive with survivin. In: Cancer Sci 99, 2008, pp 1709-1714, PMID 18537980 (Review).
  • M. Pennati et al. a .: Targeting survivin in cancer therapy. In: Expert Opin Ther Targets 12, 2008, pp. 463-476, PMID 18348682 (Review).
  • DC Altieri: Survivin, versatile modulation of cell division and apoptosis in cancer. In: Oncogene 22, 2003, pp. 8581-8589, PMID 14634620 (review).
  • AG Uren u. a .: Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. In: Curr Biol 10, 2000, pp. 1319-1328, PMID 11084331 .
  • K. Kobayashi et al. a .: Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. In: PNAS 96, 1999, pp. 1457-1462, PMID 9990045 , PMC 15484 (free full text).
  • EC LaCasse u. a .: The inhibitors of apoptosis (IAPs) and their emerging role in cancer. In: Oncogene 25, 1998, pp. 3247-2359, PMID 9916987 .
  • C. Adida et al. a .: Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. In: Am J Pathol , 152, 1998, pp. 43-49, PMID 9422522 , PMC 1858132 (free full text).

Web links

Individual evidence

  1. ↑ uni-protocol.de: Jürgen C. Becker examines immunotherapies against cancer. Retrieved September 3, 2007
  2. ↑ scinexx: arrest in the cancer cell. dated January 26, 2008.
  3. ^ A b D. C. Altieri: Validating survivin as a cancer therapeutic target. In: Nat. Rev. Cancer 3, 2003, pp. 46-54, PMID 12509766 .
  4. ^ AD Schimmer: Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. In: Cancer Res . 64, 2004, pp. 7183-7190, PMID 15492230 , doi: 10.1158 / 0008-5472.CAN-04-1918 .
  5. ↑ G. Ambrosini et al. a .: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. In: Nature Medicine . Vol. 8, 1997, pp. 917-921, PMID 9256286 .
  6. ↑ a b c S. Weikert: The apoptosis inhibitor Survivin: A tumor marker with the expression profile of a cancer / testis antigen , 9 habilitation thesis, FU Berlin, 2007.
  7. ↑ a b c M. Kappler: Molecular characterization of the IAP survivin in soft tissue sarcoma: Importance for prognosis and establishment of new therapeutic strategies. (PDF; 1.4 MB) Dissertation, University of Halle-Wittenberg, 2005.
  8. ↑ a b c curado.de of August 9, 2007: Export stop against cancer growth. Retrieved September 3, 2007
  9. ^ F. Li, DC Altieri: The cancer antiapoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression. In: Cancer Res 59, 1999, pp. 3143-3151, PMID 10397257 .
  10. ↑ UniProt O15392
  11. ↑ NE Crook u. a .: An apoptosis-inhibiting baculovirus gene with a zinc fingerlike motif. In: J. Virol. 67, 1993, pp. 2168-2174, PMID 8445726 , PMC 240327 (free full text).
  12. ↑ RJ Clem et al. a .: Control of programmed cell death by the baculovirus genes p35 and iap. In: Mol. Cell Biol. 14, 1994, pp. 5212-5222, PMID 8035800 , PMC 359040 (free full text).
  13. ↑ a b Maureen Müller: Survivin and its alternative splice variants: Investigations into their significance for cytostatic-induced apoptosis and its molecular interaction partners. (PDF; 1.8 MB) Dissertation, Heinrich Heine University Düsseldorf, 2004.
  14. ↑ L. Chantalat et al. a .: Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. In: Mol Cell 6, 2000, pp. 183-189, PMID 10949039 .
  15. ↑ apoptosis inhibitor survivin (Homo sapiens) . NCBI protein; Retrieved March 3, 2010
  16. ↑ D. Grossman et al. a .: Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. In: J. Clin. Invest. 108, 2001 pp. 991-999, PMID 11581300 , PMC 200956 (free full text).
  17. ↑ EM Conway et al. a .: Deficiency of survivin in transgenic mice exacerbates Fas-induced apoptosis via mitochondrial pathways. In: Gastroenterology . 123, 2002, pp. 619-631, PMID 12145814 .
  18. ↑ H. Marusawa et al. a .: HBXIP functions as a cofactor of survivin in apoptosis suppression. In: Embo J . 22, 2003, pp. 2729-2740, PMID 12773388 , PMC 156760 (free full text).
  19. ↑ Focus oncology: suspected cancer with survivin in the urine. ( Memento of the original from September 28, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF) 9, 2004, p. 31. @1@ 2Template: Webachiv / IABot / www.im-focus-onkologie.de
  20. ↑ SF Shariat u. a .: Urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer. In: J Urol 171, 2004, pp. 626-630, PMID 14713774 .
  21. ↑ R. Löser: About the influence of survivin expression on the survival time of patients with prostate neoplasm who were radically prostatectomized. (PDF; 888 kB) Dissertation, University of Hamburg, 2011.
  22. ^ DB Longley, PG Johnston: Molecular mechanisms of drug resistance. In: J Pathol 205, 2005, pp. 275-292, PMID 15641020 .
  23. ↑ HS Swana et al. a .: Tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. In: NEJM 341, 1999, pp. 452-453, PMID 10438269 , doi: 10.1056 / NEJM199908053410614 .
  24. ↑ A. Islam et al. a .: High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. In: Oncogene 19, 2000, pp. 617-623, PMID 10698506 , doi: 10.1038 / sj.onc.1203358 .
  25. ↑ H. Kawasaki et al. a .: Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. In: Cancer Res 58, 1998, pp. 5071-5074, PMID 9823313
  26. ↑ MH Andersen u. a .: The universal character of the tumor-associated antigen survivin. In: Clin Cancer Res 13, 2007, pp. 5991-5994, PMID 17947459 , doi: 10.1158 / 1078-0432.CCR-07-0686 (review).
  27. ↑ swisscancer.ch: Survivin as a target molecule to promote the sensitivity of tumors to chemotherapy and signal transduction via death receptor. Retrieved September 3, 2007.
  28. ↑ a b B. M. Ryan et al. a .: Survivin: a new target for anti-cancer therapy. In: Cancer Treat Rev 35, 2009, pp. 553-562, PMID 19559538 (review).
  29. ↑ New Perspectives in Cancer . (PDF) Lilly Oncology Research
  30. ↑ S. Heinzel: Targeted therapy not yet achieved. ( Memento of September 30, 2007 in the Internet Archive ) In: MMP , 27, 2004 p. 109.
  31. ↑ G. Giaccone et al. a .: Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. In: J Clin Oncol 27, 2009, pp. 4481-4486, PMID 19687333 .
  32. ↑ KD Lewis, W. Samlowski u. a .: A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. In: Investigational new drugs. Volume 29, Number 1, February 2011, pp. 161-166, doi: 10.1007 / s10637-009-9333-6 , PMID 19830389 .
  33. ↑ Y. Wang et al. a .: YM-155. In: Drugs of the Future 32, 2007, pp. 879-882, doi: 10.1358 / dof.2007.032.10.1145702 .
  34. ↑ T. Nakahara et al. a .: YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor Xenografts. In: Cancer Research 67, 2007, pp. 8014-8021; doi: 10.1158 / 0008-5472.CAN-07-1343 , PMID 17804712 .
  35. ↑ MH Andersen u. a .: Cancer treatment: the combination of vaccination with other therapies. In: Cancer Immunol Immunother 57, 2008, pp. 1735-1743, PMID 18286284 (review), PMC 2522294 (free full text).
  36. ↑ T. Hayashibara et al. a .: Resveratrol induces downregulation in survivin expression and apoptosis in HTLV-1-infected cell lines: A prospective agent for adult T cell leukemia chemotherapy. In: Nutrition and Cancer , 44, 2002, pp. 192-201, PMID 12734068 , doi: 10.1207 / S15327914NC4402_12 .