EGFR Signalling As a Negative Regulator of Notch1 Gene Transcription and Function in Proliferating Keratinocytes and Cancer

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2008 Jul 8

PMID 18604200

Citations 111

Authors

Vihren Kolev

Anna Mandinova

Juan Guinea-Viniegra

Bing Hu

Karine Lefort

Chiara Lambertini

Victor Neel

Reinhard Dummer

Erwin F Wagner

G Paolo Dotto

Affiliations

Soon will be listed here.

Abstract

The Notch1 gene has an important role in mammalian cell-fate decision and tumorigenesis. Upstream control mechanisms for transcription of this gene are still poorly understood. In a chemical genetics screen for small molecule activators of Notch signalling, we identified epidermal growth factor receptor (EGFR) as a key negative regulator of Notch1 gene expression in primary human keratinocytes, intact epidermis and skin squamous cell carcinomas (SCCs). The underlying mechanism for negative control of the Notch1 gene in human cells, as well as in a mouse model of EGFR-dependent skin carcinogenesis, involves transcriptional suppression of p53 by the EGFR effector c-Jun. Suppression of Notch signalling in cancer cells counteracts the differentiation-inducing effects of EGFR inhibitors while, at the same time, synergizing with these compounds in induction of apoptosis. Thus, our data reveal a key role of EGFR signalling in the negative regulation of Notch1 gene transcription, of potential relevance for combinatory approaches for cancer therapy.

Citing Articles

Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids.

Shimonosono M, Morimoto M, Hirose W, Tomita Y, Matsuura N, Flashner S Biomolecules. 2024; 14(9).

PMID: 39334892 PMC: 11430971. DOI: 10.3390/biom14091126.

Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma.

Britton W, Cioffi I, Stonebraker C, Spence M, Okolo O, Martin C Cancers (Basel). 2024; 16(17).

PMID: 39272905 PMC: 11394608. DOI: 10.3390/cancers16173047.

Microarray-based detection and expression analysis of drug resistance in an animal model of peritoneal metastasis from colon cancer.

Yagublu V, Bayramov B, Reissfelder C, Hajibabazade J, Abdulrahimli S, Keese M Clin Exp Metastasis. 2024; 41(5):707-715.

PMID: 38609535 PMC: 11499332. DOI: 10.1007/s10585-024-10283-5.

Signaling Pathways Controlling Axonal Wrapping in .

Baldenius M, Kautzmann S, Nanda S, Klambt C Cells. 2023; 12(21).

PMID: 37947631 PMC: 10647682. DOI: 10.3390/cells12212553.

The covert symphony: cellular and molecular accomplices in breast cancer metastasis.

Si H, Esquivel M, Mendoza Mendoza E, Roarty K Front Cell Dev Biol. 2023; 11:1221784.

PMID: 37440925 PMC: 10333702. DOI: 10.3389/fcell.2023.1221784.

References

Mandinova A, Lefort K, Tommasi di Vignano A, Stonely W, Ostano P, Chiorino G . The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response. EMBO J. 2008; 27(8):1243-54. PMC: 2367396. DOI: 10.1038/emboj.2008.45. View

Dotto G . Signal transduction pathways controlling the switch between keratinocyte growth and differentiation. Crit Rev Oral Biol Med. 2000; 10(4):442-57. DOI: 10.1177/10454411990100040201. View

Dajee M, Lazarov M, Zhang J, Cai T, Green C, Russell A . NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature. 2003; 421(6923):639-43. DOI: 10.1038/nature01283. View

Phan R, Dalla-Favera R . The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004; 432(7017):635-9. DOI: 10.1038/nature03147. View

Tergaonkar V, Perkins N . p53 and NF-kappaB crosstalk: IKKalpha tips the balance. Mol Cell. 2007; 26(2):158-9. DOI: 10.1016/j.molcel.2007.04.006. View

Lefort K, Dotto G . Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol. 2004; 14(5):374-86. DOI: 10.1016/j.semcancer.2004.04.017. View

Friday B, Adjei A . Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008; 14(2):342-6. DOI: 10.1158/1078-0432.CCR-07-4790. View

Yugawa T, Handa K, Narisawa-Saito M, Ohno S, Fujita M, Kiyono T . Regulation of Notch1 gene expression by p53 in epithelial cells. Mol Cell Biol. 2007; 27(10):3732-42. PMC: 1899981. DOI: 10.1128/MCB.02119-06. View

Artavanis-Tsakonas S, Rand M, Lake R . Notch signaling: cell fate control and signal integration in development. Science. 1999; 284(5415):770-6. DOI: 10.1126/science.284.5415.770. View

10.

Bruno T, De Nicola F, Iezzi S, Lecis D, DAngelo C, Di Padova M . Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint. Cancer Cell. 2006; 10(6):473-86. DOI: 10.1016/j.ccr.2006.10.012. View

11.

Nguyen B, Lefort K, Mandinova A, Antonini D, Devgan V, Della Gatta G . Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 2006; 20(8):1028-42. PMC: 1472299. DOI: 10.1101/gad.1406006. View

12.

Miele L, Miao H, Nickoloff B . NOTCH signaling as a novel cancer therapeutic target. Curr Cancer Drug Targets. 2006; 6(4):313-23. DOI: 10.2174/156800906777441771. View

13.

Lacouture M . Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006; 6(10):803-12. DOI: 10.1038/nrc1970. View

14.

Kalyankrishna S, Grandis J . Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006; 24(17):2666-72. DOI: 10.1200/JCO.2005.04.8306. View

15.

Reuter C, Morgan M, Eckardt A . Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br J Cancer. 2007; 96(3):408-16. PMC: 2360023. DOI: 10.1038/sj.bjc.6603566. View

16.

Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I . Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev. 2007; 21(5):562-77. PMC: 1820898. DOI: 10.1101/gad.1484707. View

17.

Dull T, Zufferey R, Kelly M, Mandel R, Nguyen M, Trono D . A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998; 72(11):8463-71. PMC: 110254. DOI: 10.1128/JVI.72.11.8463-8471.1998. View

18.

Vassilev L, Vu B, Graves B, Carvajal D, Podlaski F, Filipovic Z . In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303(5659):844-8. DOI: 10.1126/science.1092472. View

19.

Weng A, Nam Y, Wolfe M, Pear W, Griffin J, Blacklow S . Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. 2003; 23(2):655-64. PMC: 151540. DOI: 10.1128/MCB.23.2.655-664.2003. View

20.

Raman V, MARTENSEN S, Reisman D, Evron E, Odenwald W, Jaffee E . Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature. 2000; 405(6789):974-8. DOI: 10.1038/35016125. View