title: The RB-E2F1 pathway regulates autophagy.
abstract: Autophagy is a protective mechanism that renders cells viable in stressful conditions. Emerging evidence suggests that this cellular process is also a tumor suppressor pathway. Previous studies showed that cyclin-dependent kinase inhibitors (CDKI) induce autophagy. Whether retinoblastoma protein (RB), a key tumor suppressor and downstream target of CDKIs, induces autophagy is not clear. Here, we show that RB triggers autophagy and that the RB activators p16INK4a and p27/kip1 induce autophagy in an RB-dependent manner. RB binding to E2 transcription factor (E2F) is required for autophagy induction and E2F1 antagonizes RB-induced autophagy, leading to apoptosis. Downregulation of E2F1 in cells results in high levels of autophagy. Our findings indicate that RB induces autophagy by repressing E2F1 activity. We speculate that this newly discovered aspect of RB function is relevant to cancer development and therapy.
authors.affiliation: Brain Tumor Center, Departments of Carcinogenesis, and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. hjiang@mdanderson.org
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martin
authors.forename: Candelaria
authors.initials: C
authors.lastname: Gomez-Manzano
authors.forename: David G
authors.initials: DG
authors.lastname: Johnson
authors.forename: Marta
authors.initials: M
authors.lastname: Alonso
authors.forename: Erin
authors.initials: E
authors.lastname: White
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
authors.forename: Naoki
authors.initials: N
authors.lastname: Shinojima
authors.forename: Juan
authors.initials: J
authors.lastname: Fueyo
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002470:Cell Survival; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein
references.citation: Mol Cell Biol. 2004 Apr;24(7):2968-77
references.pmid: 15024084
references.citation: J Cell Biol. 2000 Sep 18;150(6):1507-13
references.pmid: 10995454
references.citation: Nat Rev Cancer. 2002 Dec;2(12):910-7
references.pmid: 12459729
references.citation: Cancer Cell. 2003 Mar;3(3):285-96
references.pmid: 12676586
references.citation: Nat Rev Cancer. 2008 Sep;8(9):714-24
references.pmid: 19143056
references.citation: Br J Cancer. 2003 Apr 22;88(8):1277-80
references.pmid: 12698196
references.citation: Carcinogenesis. 1993 Dec;14(12):2501-5
references.pmid: 8269618
references.citation: Trends Cell Biol. 2008 Nov;18(11):528-35
references.pmid: 18805009
references.citation: Int J Oncol. 1998 Mar;12(3):665-9
references.pmid: 9472109
references.citation: Oncogene. 2007 Mar 1;26(10):1492-8
references.pmid: 16953228
references.citation: Cancer Cell. 2005 Jan;7(1):51-63
references.pmid: 15652749
references.citation: Cancer Cell. 2003 Dec;4(6):422-4
references.pmid: 14706333
references.citation: J Clin Invest. 2003 Dec;112(12):1809-20
references.pmid: 14638851
references.citation: Oncogene. 2004 May 20;23(23):4107-20
references.pmid: 15064736
references.citation: Nat Rev Cancer. 2003 Feb;3(2):130-8
references.pmid: 12563312
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: Cell Cycle. 2009 Feb 15;8(4):532-5
references.pmid: 19182518
references.citation: Nature. 1992 Sep 24;359(6393):288-94
references.pmid: 1406932
references.citation: J Biol Chem. 2008 Apr 18;283(16):10892-903
references.pmid: 18281291
references.citation: Genes Dev. 2007 Jul 1;21(13):1621-35
references.pmid: 17606641
references.citation: Nat Cell Biol. 2007 Feb;9(2):218-24
references.pmid: 17237771
references.citation: Hum Mol Genet. 2001 Apr;10(7):699-703
references.pmid: 11257102
references.citation: Cell. 1978 Jan;13(1):181-8
references.pmid: 620421
references.citation: Int J Cancer. 1998 Dec 18;79(6):640-4
references.pmid: 9842975
references.citation: Curr Mol Med. 2006 Nov;6(7):731-8
references.pmid: 17100599
references.citation: Dev Cell. 2004 Apr;6(4):463-77
references.pmid: 15068787
references.citation: Genes Dev. 2004 Apr 15;18(8):862-76
references.pmid: 15078817
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3033-7
references.pmid: 1826560
references.citation: Nat Rev Mol Cell Biol. 2008 Sep;9(9):713-24
references.pmid: 18719710
references.citation: J Natl Cancer Inst. 2007 Sep 19;99(18):1410-4
references.pmid: 17848677
references.citation: Nature. 2006 Jun 15;441(7095):880-4
references.pmid: 16625205
references.citation: Cell Cycle. 2008 Apr 15;7(8):1095-103
references.pmid: 18414045
references.citation: Nature. 2008 Feb 28;451(7182):1069-75
references.pmid: 18305538
references.citation: Clin Cancer Res. 2010 Feb 15;16(4):1094-9
references.pmid: 20145169
references.citation: Cancer Res. 2001 Sep 15;61(18):6693-7
references.pmid: 11559537
references.citation: Nature. 1995 Oct 5;377(6548):441-6
references.pmid: 7566123
references.citation: J Cell Physiol. 1984 Apr;119(1):127-32
references.pmid: 6323489
references.citation: Genes Dev. 1994 Jul 1;8(13):1514-25
references.pmid: 7958836
references.citation: Genes Dev. 2009 Apr 1;23(7):798-803
references.pmid: 19279323
references.citation: J Biol Chem. 2007 Jun 22;282(25):18573-18583
references.pmid: 17442669
references.citation: Clin Cancer Res. 1997 Dec;3(12 Pt 1):2415-23
references.pmid: 9815642
references.citation: Oncogene. 1996 Dec 19;13(12):2699-705
references.pmid: 9000144
references.citation: Mol Cell Biol. 2007 Sep;27(17):6229-42
references.pmid: 17576813
references.citation: Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
references.pmid: 17717517
references.citation: Cell. 2005 Sep 23;122(6):927-39
references.pmid: 16179260
references.citation: Oncogene. 2008 Aug 14;27(35):4860-4
references.pmid: 18408756
references.citation: Autophagy. 2007 Sep-Oct;3(5):452-60
references.pmid: 17534139
references.citation: Nat Rev Cancer. 2007 Dec;7(12):961-7
references.pmid: 17972889
references.citation: Hum Genet. 1994 Oct;94(4):349-54
references.pmid: 7927327
references.citation: Nat Med. 1998 Jun;4(6):685-90
references.pmid: 9623977
references.citation: Cancer Biol Ther. 2003 Mar-Apr;2(2):124-30
references.pmid: 12750549