Apoptosis inhibitors

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Apoptosis inhibitors ( English Inhibitors of apoptosis protein, IAP ) are a family of proteins that were first discovered in baculoviruses and act as endogenous inhibitors for apoptosis ( programmed cell death ).

history

IAP- coding sequences were first discovered in 1993 in the genome of baculoviruses. It was found that IAPs are involved in suppressing cell death in baculovirus-infected host cells. Since then, many more IAP representatives have been found in different species. What these IAPs have in common is the presence of at least one BIR domain ( Baculovirus IAP repeat ), which consists of around 70 amino acids and is responsible for the inhibition of apoptosis.

The IAP family

The human IAP family currently comprises eight proteins.

  • The three IAPs XIAP , c-IAP-1 and c-IAP-2 directly inhibit caspases -3, -7 and procaspase-9
  • Survivin inhibits caspases-3, -7 and -9.
  • c-IAP-1 and c-IAP-2 are involved in the signal transduction of membrane-bound receptors, for example TNF receptor 2 (TNFR2) complex.
  • ILP2 , ML-IAP , NAIP, and BRUCE are other IAPs.

Effects

Tumor cells increased with the help of apoptosis-inhibiting their vitality and thus against immunological and cytotoxic therapies resistant . The lack of caspase activity leads to an increased resistance to the induction of apoptosis. Transformed cells overexpress only survivin and ML-IAP. Survivin is most often tumor-specifically expressed IAP. This makes it the most interesting member of this protein family and an important object of study in oncology.

Individual evidence

  1. ↑ MJ Birnbaum, RJ Clem, LK Miller: An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys / His sequence motifs. In: Journal of virology Volume 68, Number 4, April 1994, pp. 2521-2528, ISSN  0022-538X . PMID 8139034 . PMC 236730 (free full text). PDF
  2. ^ NE Crook, RJ Clem, LK Miller: An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. In: Journal of virology Volume 67, Number 4, April 1993, pp. 2168-2174, ISSN  0022-538X . PMID 8445726 . PMC 240327 (free full text). PDF
  3. ↑ a b c M. 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.
  4. ↑ a b S. Weikert: The apoptosis inhibitor Survivin: A tumor marker with the expression profile of a cancer / testis antigen. Habilitation, FU Berlin, 2007
  5. ↑ a b Q. L. Deveraux, JC Reed: IAP family proteins suppressors of apoptosis. In: Genes & development Volume 13, Number 3, February 1999, pp. 239-252, ISSN  0890-9369 . PMID 9990849 . (Review). PDF
  6. ↑ I. Tamm, Y. Wang, E. Sausville, DA Scudiero, N. Vigna, T. Oltersdorf, JC Reed: IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. In: Cancer research Volume 58, Number 23, December 1998, pp. 5315-5320, ISSN  0008-5472 . PMID 9850056 . PDF
  7. ^ A b F. Li, EJ Ackermann, CF Bennett, AL Rothermel, J. Plescia, S. Tognin, A. Villa, PC Marchisio, DC Altieri: Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. In: Nature cell biology Volume 1, Number 8, December 1999, pp. 461-466, ISSN  1465-7392 . PMID 10587640 .
  8. ↑ DP Banks, J. Plescia, DC Altieri, J. Chen, SH Rosenberg, H. Zhang, SC Ng: Survivin does not inhibit caspase-3 activity. In: Blood Volume 96, Number 12, December 2000, pp. 4002-4003, ISSN  0006-4971 . PMID 11186274 .
  9. ^ MA Verdecia, H. Huang, E. Dutil, DA Kaiser, T. Hunter, JP Noel: Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement. In: Nature Structural Biology Volume 7, Number 7, July 2000, pp. 602-608, ISSN  1072-8368 . doi : 10.1038 / 76838 . PMID 10876248 .
  10. ↑ S. Shin, BJ Sung, YS Cho, HJ Kim, NC Ha, JI Hwang, CW Chung, YK Jung, BH Oh: An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. In: Biochemistry Volume 40, Number 4, January 2001, pp. 1117-1123, ISSN  0006-2960 . PMID 11170436 .
  11. ↑ D. Vucic, HR Stennicke, MT Pisabarro, GS Salvesen, VM Dixit: ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. In: Current biology: CB Volume 10, Number 21, November 2000, pp. 1359-1366, ISSN  0960-9822 . PMID 11084335 .
  12. ^ DC Altieri: Cytokinesis, apoptosis and survivin: three for tango? In: Cell death and differentiation Volume 8, Number 1, January 2001, pp. 4-5, ISSN  1350-9047 . doi : 10.1038 / sj.cdd.4400795 . PMID 11313697 .
  13. ↑ DC Altieri: Survivin, versatile modulation of cell division and apoptosis in cancer. In: Oncogene Volume 22, Number 53, November 2003, pp. 8581-8589, ISSN  0950-9232 . doi : 10.1038 / sj.onc.1207113 . PMID 14634620 . (Review).