Membrane-Tethered Intracellular Domain of Amphiregulin Promotes Keratinocyte Proliferation

The Journal of Investigative Dermatology
S W StollJ T Elder

Abstract

The epidermal growth factor receptor (EGFR) and its ligands are essential regulators of epithelial biology, which are often amplified in cancer cells. We have previously shown that shRNA-mediated silencing of one of these ligands, amphiregulin (AREG), results in keratinocyte growth arrest that cannot be rescued by soluble extracellular EGFR ligands. To further explore the functional importance of specific AREG domains, we stably transduced keratinocytes expressing tetracycline-inducible AREG-targeted shRNA with lentiviruses expressing silencing-proof, membrane-tethered AREG cytoplasmic and extracellular domains (AREG-CTD and AREG-ECD), as well as full-length AREG precursor (proAREG). Here we show that growth arrest of AREG-silenced keratinocytes occurs in G2/M and is significantly restored by proAREG and AREG-CTD but not by AREG-ECD. Moreover, the AREG-CTD was sufficient to normalize cell cycle distribution profiles and expression of mitosis-related genes. Our findings uncover an important role of the AREG-CTD in regulating cell division, which may be relevant to tumor resistance to EGFR-directed therapies.

References

Sep 1, 1991·Experimental Cell Research·M Satoh, T Kuroiwa
Sep 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·M ShoyabG J Todaro
Sep 1, 1995·Biotechnic & Histochemistry : Official Publication of the Biological Stain Commission·J Kapuscinski
Dec 31, 1997·The Journal of Clinical Investigation·P W CookM R Pittelkow
Nov 5, 2003·The Journal of Cell Biology·Daisuke NanbaShigeki Higashiyama
Mar 3, 2004·The Journal of Cell Biology·Umut SahinCarl P Blobel
Apr 20, 2004·Seminars in Radiation Oncology·David RabenK Kian Ang
Jul 23, 2004·The New England Journal of Medicine·David CunninghamEric Van Cutsem
May 26, 2007·The American Journal of Pathology·Laure RittiéJames T Elder
Feb 15, 2008·Cancer Science·Shigeki HigashiyamaNatsuki Matsushita
Jul 18, 2009·The Journal of Investigative Dermatology·Stefan W StollJames T Elder
Oct 15, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Benoît BusserAmandine Hurbin
Oct 15, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Benoît BusserAmandine Hurbin
Nov 20, 2009·The Journal of Investigative Dermatology·Bernice Y KwongMichael Girardi
Apr 30, 2010·The Journal of Investigative Dermatology·Stefan W StollJames T Elder
Jun 10, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ingeborg TinhoferUlrich Keilholz
Jun 11, 2011·Biochimica Et Biophysica Acta·Benoit BusserAmandine Hurbin
Feb 22, 2012·Oncogene·A FreijeA Gandarillas
Apr 17, 2012·Journal of Cell Science·E Douglas RobertsonAndrey A Panteleyev
Nov 13, 2013·Annual Review of Physiology·Bhuminder Singh, Robert J Coffey

❮ Previous
Next ❯

Citations

Sep 17, 2016·F1000Research·Bhuminder SinghRobert J Coffey
Mar 4, 2020·International Journal of Molecular Medicine·Yaojia X Yaojia ChengChen Liu
Nov 17, 2020·Frontiers in Medicine·Mahmood Yaseen HachimRifat Hamoudi

❮ Previous
Next ❯

Related Concepts

Related Feeds