[en] Elongator, a multi-subunit complex assembled by the IkappaB kinase-associated protein (IKAP)/hELP1 scaffold protein is involved in transcriptional elongation in the nucleus as well as in tRNA modifications in the cytoplasm. However, the biological processes regulated by Elongator in human cells only start to be elucidated. Here we demonstrate that IKAP/hELP1 depleted colon cancer-derived cells show enhanced basal expression of some but not all pro-apoptotic p53-dependent genes such as BAX. Moreover, Elongator deficiency causes increased basal and daunomycin-induced expression of the pro-survival serum- and glucocorticoid-induced protein kinase (SGK) gene through a p53-dependent pathway. Thus, our data collectively demonstrate that Elongator deficiency triggers the activation of p53-dependent genes harbouring opposite functions with respect to apoptosis.
Otero G., Fellows J., Li Y., de Bizemont T., Dirac A.M., Gustafsson C.M., et al. Elongator, a multisubunit component of a novel RNA polymerase II holoenzyme for transcriptional elongation. Mol Cell 3 (1999) 109-118
Hawkes N.A., Otero G., Winkler G.S., Marshall N., Dahmus M.E., Krappmann D., et al. Purification and characterization of the human elongator complex. J Biol Chem 277 (2002) 3047-3052
Kim J.H., Lane W.S., and Reinberg D. Human Elongator facilitates RNA polymerase II transcription through chromatin. Proc Natl Acad Sci USA 99 (2002) 1241-1246
Petrakis T.G., Wittschieben B.O., and Svejstrup J.Q. Molecular architecture, structure-function relationship, and importance of the Elp3 subunit for the RNA binding of holo-elongator. J Biol Chem 279 (2004) 32087-32092
Wittschieben B.O., Otero G., de Bizemont T., Fellows J., Erdjument-Bromage H., Ohba R., et al. A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol Cell 4 (1999) 123-128
Winkler G.S., Kristjuhan A., Erdjument-Bromage H., Tempst P., and Svejstrup J.Q. Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proc Natl Acad Sci USA 99 (2002) 3517-3522
Kristjuhan A., Walker J., Suka N., Grunstein M., Roberts D., Cairns B.R., et al. Transcriptional inhibition of genes with severe histone h3 hypoacetylation in the coding region. Mol Cell 10 (2002) 925-933
Gilbert C., Kristjuhan A., Winkler G.S., and Svejstrup J.Q. Elongator interactions with nascent mRNA revealed by RNA immunoprecipitation. Mol Cell 14 (2004) 457-464
Metivier R., Penot G., Hubner M.R., Reid G., Brand H., Kos M., et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115 (2003) 751-763
Kouskouti A., and Talianidis I. Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J 24 (2005) 347-357
Close P., Hawkes N., Cornez I., Creppe C., Lambert C.A., Rogister B., et al. Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol Cell 22 (2006) 521-531
Huang B., Johansson M.J., and Bystrom A.S. An early step in wobble uridine tRNA modification requires the Elongator complex. RNA 11 (2005) 424-436
Rahl P.B., Chen C.Z., and Collins R.N. Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation. Mol Cell 17 (2005) 841-853
Esberg A., Huang B., Johansson M.J., and Bystrom A.S. Elevated levels of two tRNA species bypass the requirement for elongator complex in transcription and exocytosis. Mol Cell 24 (2006) 139-148
Svejstrup J.Q. Elongator complex: how many roles does it play?. Curr Opin Cell Biol 19 (2007) 331-336
Nelissen H., Fleury D., Bruno L., Robles P., De Veylder L., Traas J., et al. The elongata mutants identify a functional Elongator complex in plants with a role in cell proliferation during organ growth. Proc Natl Acad Sci USA 102 (2005) 7754-7759
Slaugenhaupt S.A., and Gusella J.F. Familial dysautonomia. Curr Opin Genet Dev 12 (2002) 307-311
Gold-von Simson G., and Axelrod F.B. Familial dysautonomia: update and recent advances. Curr Probl Pediatr Adolesc Health Care 36 (2006) 218-237
Anderson S.L., Coli R., Daly I.W., Kichula E.A., Rork M.J., Volpi S.A., et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 68 (2001) 753-758
Slaugenhaupt S.A., Blumenfeld A., Gill S.P., Leyne M., Mull J., Cuajungco M.P., et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68 (2001) 598-605
Sims III R.J., Belotserkovskaya R., and Reinberg D. Elongation by RNA polymerase II: the short and long of it. Genes Dev 18 (2004) 2437-2468
Orphanides G., LeRoy G., Chang C.H., Luse D.S., and Reinberg D. FACT, a factor that facilitates transcript elongation through nucleosomes. Cell 92 (1998) 105-116
Gomes N.P., Bjerke G., Llorente B., Szostek S.A., Emerson B.M., and Espinosa J.M. Gene-specific requirement for P-TEFb activity and RNA polymerase II phosphorylation within the p53 transcriptional program. Genes Dev 20 (2006) 601-612
Olivier S., Close P., Castermans E., de Leval L., Tabruyn S., Chariot A., et al. Raloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature. Mol Pharmacol 69 (2006) 1615-1623
Shieh S.Y., Ikeda M., Taya Y., and Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91 (1997) 325-334
el-Deiry W.S., Harper J.W., O'Connor P.M., Velculescu V.E., Canman C.E., Jackman J., et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54 (1994) 1169-1174
el-Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent J.M., et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75 (1993) 817-825
Kannan K., Amariglio N., Rechavi G., Jakob-Hirsch J., Kela I., Kaminski N., et al. DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 20 (2001) 2225-2234
Irminger-Finger I., Leung W.C., Li J., Dubois-Dauphin M., Harb J., Feki A., et al. Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis. Mol Cell 8 (2001) 1255-1266
Huang Q., Raya A., DeJesus P., Chao S.H., Quon K.C., Caldwell J.S., et al. Identification of p53 regulators by genome-wide functional analysis. Proc Natl Acad Sci USA 101 (2004) 3456-3461
Shen W.H., Wang J., Wu J., Zhurkin V.B., and Yin Y. Mitogen-activated protein kinase phosphatase 2: a novel transcription target of p53 in apoptosis. Cancer Res 66 (2006) 6033-6039
Maiyar A.C., Huang A.J., Phu P.T., Cha H.H., and Firestone G.L. p53 stimulates promoter activity of the sgk. serum/glucocorticoid-inducible serine/threonine protein kinase gene in rodent mammary epithelial cells. J Biol Chem 271 (1996) 12414-12422
Wei C.L., Wu Q., Vega V.B., Chiu K.P., Ng P., Zhang T., et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124 (2006) 207-219
Ongusaha P.P., Kim H.G., Boswell S.A., Ridley A.J., Der C.J., Dotto G.P., et al. RhoE is a pro-survival p53 target gene that inhibits ROCK I-mediated apoptosis in response to genotoxic stress. Curr Biol 16 (2006) 2466-2472
Brunet A., Park J., Tran H., Hu L.S., Hemmings B.A., and Greenberg M.E. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 21 (2001) 952-965
Chang D., Chen F., Zhang F., McKay B.C., and Ljungman M. Dose-dependent effects of DNA-damaging agents on p53-mediated cell cycle arrest. Cell Growth Differ 10 (1999) 155-162
Ljungman M., O'Hagan H.M., and Paulsen M.T. Induction of ser15 and lys382 modifications of p53 by blockage of transcription elongation. Oncogene 20 (2001) 5964-5971
Rouault J.P., Falette N., Guehenneux F., Guillot C., Rimokh R., Wang Q., et al. Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nat Genet 14 (1996) 482-486
Ljungman M., Zhang F., Chen F., Rainbow A.J., and McKay B.C. Inhibition of RNA polymerase II as a trigger for the p53 response. Oncogene 18 (1999) 583-592
Derheimer F.A., O'Hagan H.M., Krueger H.M., Hanasoge S., Paulsen M.T., and Ljungman M. RPA and ATR link transcriptional stress to p53. Proc Natl Acad Sci USA 104 (2007) 12778-12783
Miyata K., Yasukawa T., Fukuda M., Takeuchi T., Yamazaki K., Sakumi K., et al. Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A. Cell Death Differ 14 (2007) 716-726
Sulic S., Panic L., Barkic M., Mercep M., Uzelac M., and Volarevic S. Inactivation of S6 ribosomal protein gene in T lymphocytes activates a p53-dependent checkpoint response. Genes Dev 19 (2005) 3070-3082
Harris S.L., and Levine A.J. The p53 pathway: positive and negative feedback loops. Oncogene 24 (2005) 2899-2908
Bogusz A.M., Brickley D.R., Pew T., and Conzen S.D. A novel N-terminal hydrophobic motif mediates constitutive degradation of serum- and glucocorticoid-induced kinase-1 by the ubiquitin-proteasome pathway. FEBS J 273 (2006) 2913-2928
You H., Jang Y., You-Ten A.I., Okada H., Liepa J., Wakeham A., et al. p53-Dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc Natl Acad Sci USA 101 (2004) 14057-14062
Han J.A., Kim J.I., Ongusaha P.P., Hwang D.H., Ballou L.R., Mahale A., et al. P53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-induced apoptosis. EMBO J 21 (2002) 5635-5644
Benoit V., de Moraes E., Dar N.A., Taranchon E., Bours V., Hautefeuille A., et al. Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB. Oncogene 25 (2006) 5708-5718