AP4 Encodes a C-MYC-inducible Repressor of P21

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Sep 27

PMID 18818310

Citations 101

Authors

Peter Jung

Antje Menssen

Doris Mayr

Heiko Hermeking

Affiliations

Soon will be listed here.

Abstract

In the majority of human tumors, expression of the c-MYC oncogene becomes constitutive. Here, we report that c-MYC directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene. Induction of AP4 was required for c-MYC-mediated cell cycle reentry of anti-estrogen arrested breast cancer cells and mitogen-mediated repression of the CDK inhibitor p21. AP4 directly repressed p21 by occupying four CAGCTG motifs in the p21 promoter via its basic region. AP4 levels declined after DNA damage, and ectopic AP4 interfered with p53-mediated cell cycle arrest and sensitized cells to apoptosis induced by DNA damaging agents. AP4 expression blocked induction of p21 by TGF-beta in human keratinocytes and interfered with up-regulation of p21 and cell cycle arrest during monoblast differentiation. Notably, AP4 is specifically expressed in colonic progenitor and colorectal carcinoma cells. In conclusion, our results indicate that c-MYC employs AP4 to maintain cells in a proliferative, progenitor-like state.

Citing Articles

AP4 induces JNK1 and a miR-22-3p/FOSL1 feed-forward loop to activate AP-1 and promote colorectal cancer metastasis.

Chou J, Kaller M, Rokavec M, Liu F, Hermeking H Cancer Commun (Lond). 2024; 44(3):433-437.

PMID: 38225895 PMC: 10958680. DOI: 10.1002/cac2.12514.

A dynamic Boolean network reveals that the BMI1 and MALAT1 axis is associated with drug resistance by limiting miR-145-5p in non-small cell lung cancer.

Gupta S, Silveira D, Piedade G, Ostrowski M, Mombach J, Hashimoto R Noncoding RNA Res. 2023; 9(1):185-193.

PMID: 38125755 PMC: 10730431. DOI: 10.1016/j.ncrna.2023.10.008.

MYC function and regulation in physiological perspective.

Jha R, Kouzine F, Levens D Front Cell Dev Biol. 2023; 11:1268275.

PMID: 37941901 PMC: 10627926. DOI: 10.3389/fcell.2023.1268275.

Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.

Blaeschke F, Chen Y, Apathy R, Daniel B, Chen A, Chen P Cell. 2023; 186(19):4216-4234.e33.

PMID: 37714135 PMC: 10508323. DOI: 10.1016/j.cell.2023.08.013.

Squalene epoxidase/SQLE is a candidate target for treatment of colorectal cancers with mutation and elevated c- expression.

Du Y, Rokavec M, Hermeking H Int J Biol Sci. 2023; 19(13):4103-4122.

PMID: 37705742 PMC: 10496509. DOI: 10.7150/ijbs.85724.

References

Kim M, Jeong B, Lee J, Kee H, Kook H, Kim N . A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci U S A. 2006; 103(35):13074-9. PMC: 1551900. DOI: 10.1073/pnas.0601915103. View

Imai K, Okamoto T . Transcriptional repression of human immunodeficiency virus type 1 by AP-4. J Biol Chem. 2006; 281(18):12495-505. DOI: 10.1074/jbc.M511773200. View

Meyer N, Kim S, Penn L . The Oscar-worthy role of Myc in apoptosis. Semin Cancer Biol. 2006; 16(4):275-87. DOI: 10.1016/j.semcancer.2006.07.011. View

van den Brink G, Offerhaus G . The morphogenetic code and colon cancer development. Cancer Cell. 2007; 11(2):109-17. DOI: 10.1016/j.ccr.2007.01.003. View

Sansom O, Meniel V, Muncan V, Phesse T, Wilkins J, Reed K . Myc deletion rescues Apc deficiency in the small intestine. Nature. 2007; 446(7136):676-9. DOI: 10.1038/nature05674. View

Jung P, Verdoodt B, Bailey A, Yates 3rd J, Menssen A, Hermeking H . Induction of cullin 7 by DNA damage attenuates p53 function. Proc Natl Acad Sci U S A. 2007; 104(27):11388-93. PMC: 2040908. DOI: 10.1073/pnas.0609467104. View

Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A . Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle. 2007; 6(13):1586-93. DOI: 10.4161/cc.6.13.4436. View

Menssen A, Epanchintsev A, Lodygin D, Rezaei N, Jung P, Verdoodt B . c-MYC delays prometaphase by direct transactivation of MAD2 and BubR1: identification of mechanisms underlying c-MYC-induced DNA damage and chromosomal instability. Cell Cycle. 2007; 6(3):339-52. DOI: 10.4161/cc.6.3.3808. View

Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett J, Obaya A . Identification of CDK4 as a target of c-MYC. Proc Natl Acad Sci U S A. 2000; 97(5):2229-34. PMC: 15783. DOI: 10.1073/pnas.050586197. View

10.

Berns K, Hijmans E, Koh E, Daley G, Bernards R . A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts. Oncogene. 2000; 19(29):3330-4. DOI: 10.1038/sj.onc.1203639. View

11.

Massague J, Blain S, Lo R . TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000; 103(2):295-309. DOI: 10.1016/s0092-8674(00)00121-5. View

12.

Gartel A, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F . Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc Natl Acad Sci U S A. 2001; 98(8):4510-5. PMC: 31865. DOI: 10.1073/pnas.081074898. View

13.

Venditti M, Iwasiow B, Orr F, Shiu R . C-myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells. Int J Cancer. 2002; 99(1):35-42. DOI: 10.1002/ijc.10269. View

14.

Carroll J, Swarbrick A, Musgrove E, Sutherland R . Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens. Cancer Res. 2002; 62(11):3126-31. View

15.

Seoane J, Le H, Massague J . Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature. 2002; 419(6908):729-34. DOI: 10.1038/nature01119. View

16.

van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A . The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002; 111(2):241-50. DOI: 10.1016/s0092-8674(02)01014-0. View

17.

Herold S, Wanzel M, Beuger V, Frohme C, Beul D, Hillukkala T . Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol Cell. 2002; 10(3):509-21. DOI: 10.1016/s1097-2765(02)00633-0. View

18.

Wu S, Cetinkaya C, Munoz-Alonso M, von der Lehr N, Bahram F, Beuger V . Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene. 2003; 22(3):351-60. DOI: 10.1038/sj.onc.1206145. View

19.

Siegel P, Massague J . Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003; 3(11):807-21. DOI: 10.1038/nrc1208. View

20.

Sansom O, Reed K, Hayes A, Ireland H, Brinkmann H, Newton I . Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 2004; 18(12):1385-90. PMC: 423189. DOI: 10.1101/gad.287404. View