BECN1 explained

Beclin-1 is a protein that in humans is encoded by the BECN1 gene.^{[1] [2]} Beclin-1 is a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6)  and BEC-1 in the C. elegans nematode.^[3] This protein interacts with either BCL-2 or PI3k class III, playing a critical role in the regulation of both autophagy and cell death.

Role in disease

Beclin-1 plays an important role in tumorigenesis, and neurodegeneration, being implicated in the autophagic programmed cell death.^[4] Ovarian cancer with upregulated autophagy has a less aggressive behavior and is more responsive to chemotherapy.^[5]

Schizophrenia is associated with low levels of Beclin-1 in the hippocampus of those affected, which causes diminished autophagy which in turn results in increased neuronal cell death.^[6]

Interactions

BECN1 has been shown to interact with:

• Bcl-2
• BCL2L2^[7]
• GOPC^[8]
• MAP1LC3A
• Rubicon^[9]
• UVRAG

Modulators

Trehalose: Trehalose reduces p62/Beclin-1 ratio and increases autophagy in the frontal cortex of ICR mice, possibly by increasing Beclin-1.^[10]

Further reading

• Funderburk SF, Wang QJ, Yue Z . The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond . Trends in Cell Biology . 20 . 6 . 355–62 . June 2010 . 20356743 . 3781210 . 10.1016/j.tcb.2010.03.002 .
• Rommens JM, Durocher F, McArthur J, Tonin P, LeBlanc JF, Allen T, Samson C, Ferri L, Narod S, Morgan K . Generation of a transcription map at the HSD17B locus centromeric to BRCA1 at 17q21 . Genomics . 28 . 3 . 530–42 . August 1995 . 7490091 . 10.1006/geno.1995.1185 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B . Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21 . Genomics . 59 . 1 . 59–65 . July 1999 . 10395800 . 10.1006/geno.1999.5851 . free .
• Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B . Induction of autophagy and inhibition of tumorigenesis by beclin 1 . Nature . 402 . 6762 . 672–6 . December 1999 . 10604474 . 10.1038/45257 . 1999Natur.402..672L . 4423132 .
• Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T . Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network . EMBO Reports . 2 . 4 . 330–5 . April 2001 . 11306555 . 1083858 . 10.1093/embo-reports/kve061 .
• Liang XH, Yu J, Brown K, Levine B . Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function . Cancer Research . 61 . 8 . 3443–9 . April 2001 . 11309306 .
• Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ . Use of chromatin immunoprecipitation to clone novel E2F target promoters . Molecular and Cellular Biology . 21 . 20 . 6820–32 . October 2001 . 11564866 . 99859 . 10.1128/MCB.21.20.6820-6832.2001 .
• Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N . A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice . Neuron . 35 . 5 . 921–33 . August 2002 . 12372286 . 10.1016/S0896-6273(02)00861-9 . 10534933 . free .
• Song H, Xia SL, Liao C, Li YL, Wang YF, Li TP, Zhao MJ . Genes encoding Pir51, Beclin 1, RbAp48 and aldolase b are up or down-regulated in human primary hepatocellular carcinoma . World Journal of Gastroenterology . 10 . 4 . 509–13 . February 2004 . 14966907 . 4716970 . 10.3748/wjg.v10.i4.509 . free .
• Scarlatti F, Bauvy C, Ventruti A, Sala G, Cluzeaud F, Vandewalle A, Ghidoni R, Codogno P . Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1 . The Journal of Biological Chemistry . 279 . 18 . 18384–91 . April 2004 . 14970205 . 10.1074/jbc.M313561200 . free .
• Furuya D, Tsuji N, Yagihashi A, Watanabe N . Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity . Experimental Cell Research . 307 . 1 . 26–40 . July 2005 . 15922724 . 10.1016/j.yexcr.2005.02.023 .
• Kruse KB, Brodsky JL, McCracken AA . Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ . Molecular Biology of the Cell . 17 . 1 . 203–12 . January 2006 . 16267277 . 1345659 . 10.1091/mbc.E04-09-0779 .
• Zeng X, Overmeyer JH, Maltese WA . Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking . Journal of Cell Science . 119 . Pt 2 . 259–70 . January 2006 . 16390869 . 10.1242/jcs.02735 . free .
• Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, MacDonald M, Yankner B, Yuan J . Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1 . The Journal of Biological Chemistry . 281 . 20 . 14474–85 . May 2006 . 16522639 . 10.1074/jbc.M600364200 . free .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Daniel F, Legrand A, Pessayre D, Vadrot N, Descatoire V, Bernuau D . Partial Beclin 1 silencing aggravates doxorubicin- and Fas-induced apoptosis in HepG2 cells . World Journal of Gastroenterology . 12 . 18 . 2895–900 . May 2006 . 16718815 . 4087807 . 10.3748/wjg.v12.i18.2895 . free .

Notes and References

1. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B . Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein . Journal of Virology . 72 . 11 . 8586–96 . November 1998 . 9765397 . 110269 . 10.1128/JVI.72.11.8586-8596.1998.
2. Web site: Entrez Gene: BECN1 beclin 1 (coiled-coil, myosin-like BCL2 interacting protein).
3. Takacs-Vellai K, Vellai T, Puoti A, Passannante M, Wicky C, Streit A, Kovacs AL, Müller F . Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans . Current Biology . 15 . 16 . 1513–7 . August 2005 . 16111945 . 10.1016/j.cub.2005.07.035 . 7404414 . free . 2005CBio...15.1513T .
4. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z . Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex . Nature Cell Biology . 11 . 4 . 468–76 . April 2009 . 19270693 . 2664389 . 10.1038/ncb1854 .
5. Valente G, Morani F, Nicotra G, Fusco N, Peracchio C, Titone R, Alabiso O, Arisio R, Katsaros D, Benedetto C, Isidoro C . Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer . BioMed Research International . 2014 . 462658 . 2014 . 25136588 . 4127242 . 10.1155/2014/462658 . free .
6. Merenlender-Wagner A, Malishkevich A, Shemer Z, Udawela M, Gibbons A, Scarr E, Dean B, Levine J, Agam G, Gozes I . Autophagy has a key role in the pathophysiology of schizophrenia . Molecular Psychiatry . 20 . 1 . 126–32 . February 2015 . 24365867 . 4320293 . 10.1038/mp.2013.174 .
7. Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, Hirsch JA, Stein R, Pinkas-Kramarski R . Differential interactions between Beclin 1 and Bcl-2 family members . Autophagy . 3 . 6 . 561–8 . 2007 . 17643073 . 10.4161/auto.4713 . free .
8. Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N . A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice . Neuron . 35 . 5 . 921–33 . August 2002 . 12372286 . 10.1016/S0896-6273(02)00861-9 . 10534933 . free .
9. Chang . Chunmei . Young . Lindsey N. . Morris . Kyle L. . von Bülow . Sören . Schöneberg . Johannes . Yamamoto-Imoto . Hitomi . Oe . Yukako . Yamamoto . Kentaro . Nakamura . Shuhei . Stjepanovic . Goran . Hummer . Gerhard . 2019-01-17 . Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics . Molecular Cell . 73 . 2 . 339–353.e6 . 10.1016/j.molcel.2018.10.035 . 1097-4164 . 6450660 . 30581147.
10. Kara NZ, Toker L, Agam G, Anderson GW, Belmaker RH, Einat H . Trehalose induced antidepressant-like effects and autophagy enhancement in mice . Psychopharmacology . 229 . 2 . 367–75 . September 2013 . 23644913 . 10.1007/s00213-013-3119-4 . 17641899 .