Skip to main content
SpringerLink
Log in
Book cover

Encyclopedia of Signaling Molecules pp 1–10Cite as

C-FLIP

  • Living reference work entry
  • First Online:

  • 188 Accesses

Synonyms

CASJ; Casper; Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; CLARP; iFLICE; FLAME-1; MRIT; Usurpin

Integration of the Mitochondrial and Death Receptors (DRs) Pathways and Role of c-FLIP

Two major signaling pathways, the intrinsic or mitochondrial pathway and the extrinsic or cell surface DRs pathway, regulate apoptosis (Fig. 1) (Lavrik et al. 2005; Micheau and Tschopp 2003; Safa et al. 2008). In the intrinsic pathway, various anti- and pro-apoptotic members of the Bcl-2 family form an interactive network that finally regulates the release of apoptosis-triggering factors such as cytochrome c, apoptosis-inducing factors including Smac/DIABLO, HtrA2/Omi, and Endonuclease G (endoG) from the mitochondria to the cytosol (Vaux 2011; Plati et al. 2011). Upon release, cytochrome cand dATP bind to apoptotic proteinase-activating factor-1 (Apaf-1), and this complex along with adenine nucleotides forms the apoptosome and promotes procaspase-9 autoactivation...

This is a preview of subscription content, log in via an institution.

References

  • Bagnoli M, Canevari S, Mezzanzanica D. Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol. 2010;42:210–3. doi:10.1016/j.biocel.2009.11.015.

    Article  CAS  PubMed  Google Scholar 

  • Cain K, Bratton SB, Langlais C, Walker G, Brown DG, Sun XM, Cohen GM. Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes. J Biol Chem. 2000;275:6067–70.

    Article  CAS  PubMed  Google Scholar 

  • Chang DW1, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart Bc, Yaish-Ohad S. et al. c-FLIOL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 2002;21:3704–14.

    Google Scholar 

  • Cao X, Pobezinskaya YL, Morgan MJ, Liu ZG. The role of TRADD in TRAIL-induced apoptosis and signaling. FASEB J. 2011;4:1353–8. 10.1096/fj.10-170480.

    Article  Google Scholar 

  • Day TW, Najafi F, Wu CH, Safa AR. Cellular FLICE-like inhibitory protein (c-FLIP): a novel target for Taxol-induced apoptosis. Biochem Pharmacol. 2006;71:1551–61.

    Article  CAS  PubMed  Google Scholar 

  • Du X, Bao G, He X, Zhao H, Yu F, Qiao Q, et al. Expression and biological significance of c-FLIP in human hepatocellular carcinomas. J Exp Clin Cancer Res. 2009;28:24. 10.1186/1756-9966-28-24.

    Article  PubMed  PubMed Central  Google Scholar 

  • El-Gazzar A, Wittinger M, Perco P, Anees M, Horvat R, Mikulits W, et al. The role of c-FLIP(L) in ovarian cancer: chaperoning tumor cells from immunosurveillance and increasing their invasive potential. Gynecol Oncol. 2010;117:451–9. 10.1016/j.ygyno.2010.02.024.

    Article  CAS  PubMed  Google Scholar 

  • Ewald F, Annemann M, Pils MC, Plaza-Sirvent C, Neff F, Erck C, Reinhold D, Schmitz I. Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice. Cell Death Dis. 2014;5:e1168. 10.1038/cddis.2014.138.

    Article  CAS  PubMed  Google Scholar 

  • Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43:449–63. 10.1016/j.molcel.2011.06.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilot D, Serandour AL, Ilyin GP, Lagadic-Gossmann D, Loyer P, Corlu A, et al. A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes. Carcinogenesis. 2005;26:2086–94.

    Article  CAS  PubMed  Google Scholar 

  • Golan-Gerstl R, Wallach-Dayan SB, Zisman P, Cardoso WV, Goldstein RH, Breuer R. Cellular FLICE-like inhibitory protein deviates myofibroblast Fas-induced apoptosis toward proliferation during lung fibrosis. Am J Respir Cell Mol Biol. 2012;47:271–9.

    Google Scholar 

  • Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN. c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem. 2005;280:14507–13.

    Article  CAS  PubMed  Google Scholar 

  • Golks A, Brenner D, Krammer PH, Lavrik IN. The c-FLIP-NH2 terminus (p22-FLIP) induces NF-κB activation. J Exp Med. 2006;203:1295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimm S. The ER-mitochondria interface: the social network of cell death. Biochim Biophys Acta. 2012;1823:327–34. 10.1016/j.bbamcr.2011.11.018.

    Article  CAS  PubMed  Google Scholar 

  • Haimerl F, Erhardt A, Sass G, Tiegs G. Down-regulation of the de-ubiquitinating enzyme ubiquitin-specific protease 2 contributes to tumor necrosis factor-alpha-induced hepatocyte survival. J Biol Chem. 2009;284:495–4. 10.1074/jbc.M803533200.

    Article  CAS  PubMed  Google Scholar 

  • He MX, He YW. A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes. Cell Death Differ. 2013;2:188–97. 10.1038/cdd.2012.148.

    Article  Google Scholar 

  • Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, et al. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–5.

    Article  CAS  PubMed  Google Scholar 

  • Kang HK, Ecklund D, Liu M, Datta SK. Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells. Arthritis Res Ther. 2009;11:R59. 10.1186/ar2682.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kataoka T, Tschopp J. N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway. Mol Cell Biol. 2004;24:2627–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kerr E, Holohan C, McLaughlin KM, Majkut J, Dolan S, Redmond K, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19:1317–27. 10.1038/cdd.2012.8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim MJ, Kim HB, Bae JH, Lee JW, Park SJ, et al. Sensitization of human K562 leukemic cells to TRAIL-induced apoptosis by inhibiting the DNA-PKcs/Akt-mediated cell survival pathway. Biochem Pharmacol. 2009;78:573–82.

    Article  CAS  PubMed  Google Scholar 

  • Korkolopoulou P, Saetta AA, Levidou G, Gigelou F, Lazaris A, Thymara I, et al. c-FLIP expression in colorectal carcinomas: association with Fas/FasL expression and prognostic implications. Histopathology. 2007;51:150–6. 10.1038/cdd.2012.8.

    Article  CAS  PubMed  Google Scholar 

  • Krammer PH, Kamiński M, Kiessling M, Gülow K. No life without death. Adv Cancer Res. 2007;97:111–38.

    Article  CAS  PubMed  Google Scholar 

  • Lavrik IN, Krammer PH. Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 2012;19:36–41.

    Article  CAS  PubMed  Google Scholar 

  • Lavrik I, Golks A, Krammer PH. Death receptor signaling. J Cell Sci. 2005;118:265–67.

    Google Scholar 

  • Leverkus M, Diessenbacher P, Geserick P. FLIPing the coin? Death receptor-mediated signals during skin tumorigenesis. Exp Dermatol. 2008;17:614–22.

    Google Scholar 

  • Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell. 1996;86:147–57.

    Article  CAS  PubMed  Google Scholar 

  • Mezache L, Mikhail M, Garofalo M, Nuovo GJ. Reduced miR-512 and the elevated expression of its targets cFLIP and MCL1 localize to neurons with hyperphosphorylated tau protein in Alzheimer disease. Appl Immunohistochem Mol Morphol. 2015;23:615–23.

    Article  CAS  PubMed  Google Scholar 

  • Micheau O. Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert Opin Ther Targets. 2003;7:559–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12:823–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naito M, Katayama R, Ishioka T, Takada R, Fujita N, Tsuruo T, et al. Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signaling. Mol Cell Biol. 2004;24:8418–27. 10.1242/jcs.058602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakajima A, Komazawa-Sakon S, Takekawa M, Sasazuki T, Yeh WC, Yagita H, et al. An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J. 2006;25:5549–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakajima A, Kojima Y, Nakayama M, Yagita H, Okumura K, Nakano H. Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells. Oncogene. 2008;27:76–84.

    Article  CAS  PubMed  Google Scholar 

  • Oztürk S, Schleich K, Lavrik IN. Cellular FLICE-like inhibitory proteins (c-FLIPs): fine-tuners of life and death decisions. Exp Cell Res. 2012;318:1324–31. 10.1016/j.yexcr.2012.01.019.

    Article  PubMed  Google Scholar 

  • Pallares J, Llobet D, Santacana M, Eritja N, Velasco A, Cuevas D, Lopez S, Palomar-Asenjo V, Yeramian A, Dolcet X. Matias-Guiu X. CK2beta is expressed in endometrial carcinoma and has a role in apoptosis resistance and cell proliferation. Am J Pathol. 2009;174:287–96. 10.2353/ajpath.2009.080552.

    Google Scholar 

  • Peter ME. The flip side of FLIP. Biochem J. 2004;382(Pt 2):e1–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;2011(3):279–96.

    Article  Google Scholar 

  • Quintavalle C, Incoronato M, Puca L, Acunzo M, Zanca C, Romano G, et al. c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity. Cell Death Differ. 2010;17:1908–16.

    Google Scholar 

  • Ranjan K, Pathak C. Expression of FADD and cFLIPL balances mitochondrial integrity and redox signaling to substantiate apoptotic cell death. Mol Cell Biochem. 2016a;422:135–50.

    Article  CAS  PubMed  Google Scholar 

  • Ranjan K, Pathak C. Expression of cFLIPL determines the basal interaction of Bcl-2 with Beclin-1 and regulates p53 dependent ubiquitination of Beclin-1 during autophagic stress. J Cell Biochem. 2016b;117:1757–68. 10.1002/jcb.25474.

    Article  CAS  PubMed  Google Scholar 

  • Reubold TF, Eschenburg S. A molecular view on signal transduction by the apoptosome. Cell Signal. 2012;24:1420–5.

    Article  CAS  PubMed  Google Scholar 

  • Safa AR. c-FLIP, a master anti-apoptotic regulator. Exp Oncol. 2012;34:176–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Safa AR. Roles of c-FLIP in apoptosis, necroptosis, and autophagy. J Carcinog Mutagen. 2013; Suppl 6. pii: 003. 10.4172/2157-2518.S6-003.

    PubMed  PubMed Central  Google Scholar 

  • Safa AR, Pollok KE. Targeting the anti-apoptotic protein c-FLIP for cancer therapy. Cancers (Basel). 2011;3:1639–71. 10.3390/cancers3021639.

    Article  CAS  Google Scholar 

  • Safa AR, Day TW, Wu CH. Cellular FLICE-like inhibitory protein (c-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets. 2008;8:37–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17:1675–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seidelin JB, Coskun M, Vainer B, Riis L, Soendergaard C, Nielsen OH. ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis. J Mol Med (Berl). 2013;91:839–49. 10.1007/s00109-013-1003-7. Epub 2013 Feb 1.

    Article  CAS  Google Scholar 

  • Silke J, Strasser A. The FLIP side of life. Sci Signal. 2013;6:pe2. 10.1126/scisignal.2003845.

    PubMed  Google Scholar 

  • Tao J, Dong J, Li Y, Liu YQ, Yang J, Wu Y, et al. Up-regulation of cellular FLICE-inhibitory protein in peripheral blood B lymphocytes in patients with systemic lupus erythematosus is associated with clinical characteristics. J Eur Acad Dermatol Venereol. 2009;23:433–7.

    Article  CAS  PubMed  Google Scholar 

  • Telieps T, Ewald F, Gereke M, Annemann M, Rauter Y, Schuster M, et al. c-FLIPR modulates cell death induction upon T-cell activation and infection. Eur J Immunol. 2013;43:1499–510. 10.1002/eji.201242819.

    Article  CAS  PubMed  Google Scholar 

  • Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, et al. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell. 2011;43:432–48. 10.1016/j.molcel.2011.06.006.

    Article  CAS  PubMed  Google Scholar 

  • Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997;386:517–21.

    Article  CAS  PubMed  Google Scholar 

  • Tian F, Lu JJ, Wang L, Li L, Yang J, Li Y, et al. Expression of c-FLIP in malignant melanoma, and its relationship with the clinicopathological features of the disease. Clin Exp Dermatol. 2012;37:259–65. 10.1111/j.1365-2230.2011.04238.x.

    Article  CAS  PubMed  Google Scholar 

  • Trivedi R, Mishra DP. Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells. Front Oncol. 2015;5:69. 10.3389/fonc.2015.00069.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vaux DL. Apoptogenic factors released from mitochondria. Biochim Biophys Acta. 2011;13:546–50. 10.1016/j.bbamcr.2010.08.002.

    Article  Google Scholar 

  • Walsh CM, Edinger AL. The complex interplay between autophagy, apoptosis, and necrotic signals promotes T-cell homeostasis. Immunol Rev. 2010;236:95–109. 10.1111/j.1600-065X.2010.00919.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin. 2008;29:1275–88.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang W, Zhou J, Shi J, Zhang Y, Liu S, Liu Y, et al. Human T-cell leukemia virus type 1 Tax-deregulated autophagy pathway and c-FLIP expression contribute to resistance against death receptor-mediated apoptosis. J Virol. 2014;88:2786–98. 10.1128/JVI.03025-13.

    Google Scholar 

  • Xiao J, Moon M, Yan L, Nian M, Zhang Y, Liu C, et al. Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. Basic Res Cardiol. 2012;107:239. 10.1007/s00395-011-0239-z.

    Article  PubMed  Google Scholar 

  • Yang A, Wilson NS, Ashkenazi A. Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Curr Opin Cell Biol. 2010;22:837–44. 10.1016/j.ceb.2010.08.001.

    Article  CAS  PubMed  Google Scholar 

  • Yao Q, Du J, Lin J, Luo Y, Wang Y, Liu Y, et al. Prognostic significance of TRAIL signalling molecules in cervical squamous cell carcinoma. J Clin Pathol. 2016;69:122–7. 10.1136/jclinpath-2014-202811.

    Article  CAS  PubMed  Google Scholar 

  • Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A, et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity. 2000;12:633–42.

    Article  CAS  PubMed  Google Scholar 

  • Yu JW, Shi Y. FLIP and the death effector domain family. Oncogene. 2008;27:6216–27. 10.1038/onc.2008.299.

    Article  CAS  PubMed  Google Scholar 

  • Yuan S, Topf M, Reubold TF, Eschenburg S, Akey CW. Changes in apaf-1 conformation that drive apoptosome assembly. Biochemistry. 2013;52:2319–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zang F, Wei X, Sun B. Relationship of c-FLIPL protein expression with molecular subtyping and clinical prognosis in invasive breast cancer. Zhonghua Bing Li Xue Za Zhi. 2014;43:442–6.

    Google Scholar 

Download references

Acknowledgment

I would like to thank Dr. Mary D. Kraeszig for her editorial assistance. The work in the author’s laboratory was supported by research grants from the National Cancer Institute (CA 080734, CA 90878, and CA 101743), Department of Defense (DOD) (OC 06095), and the Indiana University Cancer Center Translational Research Acceleration Collaboration (ITRAC) initiative.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN, 46202, USA

    Ahmad R. Safa

  2. Indiana University Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN, 46202, USA

    Ahmad R. Safa

Authors
  1. Ahmad R. Safa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmad R. Safa .

Editor information

Editors and Affiliations

  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media LLC

About this entry

Cite this entry

Safa, A.R. (2016). C-FLIP. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_101547-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_101547-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Online ISBN: 978-1-4614-6438-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation