An ARF/CtBP2 Complex Regulates BH3-only Gene Expression and P53-independent Apoptosis

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2009 Oct 3

PMID 19798104

Citations 36

Authors

R C Kovi

S Paliwal

S Pande

S R Grossman

Affiliations

Soon will be listed here.

Abstract

The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent functions. The corepressor C-terminal binding protein (CtBP) interacts with ARF, resulting in proteasome-mediated degradation of CtBP. ARF can induce apoptosis in p53-null colon cancer cells, in a manner dependent on ARF interaction with CtBP. Bik was uniquely identified in an apoptotic gene array as coordinately upregulated in colon cancer cells after either CtBP2 knockdown or ARF overexpression. Validating the array findings, ARF induced Bik mRNA and protein expression, and this activity required an intact CtBP binding domain. Apoptosis induced by CtBP deficiency was substantially impaired when Bik expression was simultaneously silenced. An analysis of the Bik promoter revealed binding sites for the CtBP-interacting basic Kruppel-like factor (BKLF). A Bik promoter luciferase reporter was repressed by BKLF and CtBP2, and ARF reversed CtBP-associated repression. Chromatin immunoprecipitation analyses showed that CtBP was recruited to the Bik promoter largely by BKLF. Expression profiling of BH3-only gene expression in ARF-expressing or CtBP-deficient cells revealed that Bik was uniquely regulated by ARF/CtBP in colon cancer cells, whereas additional BH3-only proteins (Bim, Bmf) showed CtBP-dependent repression in osteosarcoma cells. ARF antagonism of CtBP repression of Bik and other BH3-only genes may have a critical role in ARF-induced p53-independent apoptosis and tumor suppression.

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References

Tong Y, Yang Q, Vater C, Venkatesh L, Custeau D, Chittenden T . The pro-apoptotic protein, Bik, exhibits potent antitumor activity that is dependent on its BH3 domain. Mol Cancer Ther. 2002; 1(2):95-102. View

Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S . Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002; 2(3):183-92. DOI: 10.1016/s1535-6108(02)00127-7. View

Sharpless N, DePinho R . The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev. 1999; 9(1):22-30. DOI: 10.1016/s0959-437x(99)80004-5. View

Kumar V, Carlson J, Ohgi K, Edwards T, Rose D, Escalante C . Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase. Mol Cell. 2002; 10(4):857-69. DOI: 10.1016/s1097-2765(02)00650-0. View

Bouillet P, Metcalf D, Huang D, Tarlinton D, Kay T, Kontgen F . Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science. 1999; 286(5445):1735-8. DOI: 10.1126/science.286.5445.1735. View

Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown J . Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998; 282(5393):1497-501. DOI: 10.1126/science.282.5393.1497. View

Paliwal S, Pande S, Kovi R, Sharpless N, Bardeesy N, Grossman S . Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis. Mol Cell Biol. 2006; 26(6):2360-72. PMC: 1430274. DOI: 10.1128/MCB.26.6.2360-2372.2006. View

Burri N, Shaw P, Bouzourene H, Sordat I, Sordat B, Gillet M . Methylation silencing and mutations of the p14ARF and p16INK4a genes in colon cancer. Lab Invest. 2001; 81(2):217-29. DOI: 10.1038/labinvest.3780230. View

Sturm I, Stephan C, Gillissen B, Siebert R, Janz M, Radetzki S . Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell Death Differ. 2005; 13(4):619-27. DOI: 10.1038/sj.cdd.4401782. View

10.

Castells A, Ino Y, Louis D, Ramesh V, Gusella J, Rustgi A . Mapping of a target region of allelic loss to a 0.5-cM interval on chromosome 22q13 in human colorectal cancer. Gastroenterology. 1999; 117(4):831-7. DOI: 10.1016/s0016-5085(99)70341-0. View

11.

Jeffers J, Parganas E, Lee Y, Yang C, Wang J, Brennan J . Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell. 2003; 4(4):321-8. DOI: 10.1016/s1535-6108(03)00244-7. View

12.

Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman R, Frisch S . C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci U S A. 2003; 100(8):4568-73. PMC: 153596. DOI: 10.1073/pnas.0830998100. View

13.

Germain M, Mathai J, Shore G . BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. J Biol Chem. 2002; 277(20):18053-60. DOI: 10.1074/jbc.M201235200. View

14.

Quinlan K, Verger A, Kwok A, Lee S, Perdomo J, Nardini M . Role of the C-terminal binding protein PXDLS motif binding cleft in protein interactions and transcriptional repression. Mol Cell Biol. 2006; 26(21):8202-13. PMC: 1636740. DOI: 10.1128/MCB.00445-06. View

15.

Coultas L, Bouillet P, Stanley E, Brodnicki T, Adams J, Strasser A . Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Mol Cell Biol. 2004; 24(4):1570-81. PMC: 344198. DOI: 10.1128/MCB.24.4.1570-1581.2004. View

16.

Schaeper U, Boyd J, Verma S, Uhlmann E, Subramanian T, Chinnadurai G . Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc Natl Acad Sci U S A. 1995; 92(23):10467-71. PMC: 40632. DOI: 10.1073/pnas.92.23.10467. View

17.

Shimazu T, Degenhardt K, Nur-E-Kamal A, Zhang J, Yoshida T, Zhang Y . NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes Dev. 2007; 21(8):929-41. PMC: 1847711. DOI: 10.1101/gad.1522007. View

18.

Cory S, Huang D, Adams J . The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003; 22(53):8590-607. DOI: 10.1038/sj.onc.1207102. View

19.

Chen Y, Paliwal S, Draheim K, Grossman S, Lewis B . p19Arf inhibits the invasion of hepatocellular carcinoma cells by binding to C-terminal binding protein. Cancer Res. 2008; 68(2):476-82. PMC: 2376045. DOI: 10.1158/0008-5472.CAN-07-1960. View

20.

Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 1998; 94(4):481-90. DOI: 10.1016/s0092-8674(00)81589-5. View