Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression.

Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Research Abstract Details 

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Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Abstract Text:

Yun-wu Zhang,Ruishan Wang,Qiang Liu,Han Zhang,Francesca-Fang Liao,Huaxi Xu,

Presenilins (PS, PS1/PS2) are necessary for the proteolytic activity of gamma-secretase, which cleaves multiple type I transmembrane proteins including Alzheimer's beta-amyloid precursor protein (APP), Notch, ErbB4, etc. Cleavage by PS/gamma-secretase releases the intracellular domain (ICD) of its substrates. Notch ICD translocates into the nucleus to regulate expression of genes important for development. However, the patho/physiological role of other ICDs, especially APP ICD (AICD), in regulating gene expression remains controversial because evidence supporting this functionality stems mainly from studies performed under supraphysiological conditions. EGF receptor (EGFR) is up-regulated in a wide variety of tumors and hence is a target for cancer therapeutics. Abnormal expression/activation of EGFR contributes to keratinocytic carcinomas, and mice with reduced PS dosages have been shown to develop skin tumors. Here we demonstrate that the levels of PS and EGFR in the skin tumors of PS1(+/-)/ PS2(-/-) mice and the brains of PS1/2 conditional double knockout mice are inversely correlated. Deficiency in PS/gamma-secretase activity or APP expression results in a significant increase of EGFR in fibroblasts. Importantly, we show that AICD mediates transcriptional regulation of EGFR. Furthermore, we provide in vivo evidence demonstrating direct binding of endogenous AICD to the EGFR promoter. Our results indicate an important role of PS/gamma-secretase-generated APP metabolite AICD in gene transcription and in EGFR-mediated tumorigenesis.

Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Publishing Authors By Initials

YW Zhang,R Wang,Q Liu,H Zhang,FF Liao,H Xu,

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: receptor, epidermal growth factor research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: receptor, epidermal growth factor research

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Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 10613-8

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 7

MONTH: 06

YEAR: 2007

Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Keywords Mesh Terms:

KEYWORDS: Receptor, Epidermal Growth Factor

MESH TERMS: metabolism

Chemical & Substance for Abstract: Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Information

Substance Name: Amyloid Precursor Protein Secretases

Registry Number: EC 3.4.-

Grant and Affiliation Information for Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression.

AFFILIATION: Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, CA 92037, USA. yunzhang@xmu.edu.cn

Country: United States

AGENCY: United States NINDS

GRANT: R01 NS054880

ACRONYM: NS

MEDLINETA: Proc Natl Acad Sci U S A

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