Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes

Roger Lee; Sandy Y Chang; Hung Trinh; Yiping Tu; Andrew C White; Brandon S.J Davies; Martin O Bergo; Loren G Fong; William E Lowry; Stephen G Young

doi:10.1093/hmg/ddq036

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Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes

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Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes

Roger Lee, Sandy Y Chang, Hung Trinh, Yiping Tu, Andrew C White, Brandon S.J Davies, Martin O Bergo, Loren G Fong, William E Lowry and Stephen G Young

Human molecular genetics, Vol.19(8), pp.1603-1617

04/15/2010

DOI: 10.1093/hmg/ddq036

PMCID: PMC2846164

PMID: 20106865

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Abstract

The modification of proteins with farnesyl or geranylgeranyl lipids, a process called protein prenylation, facilitates interactions of proteins with membrane surfaces. Protein prenylation is carried out by a pair of cytosolic enzymes, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase-I). FTase and GGTase-I have attracted interest as therapeutic targets for both cancer and progeria, but very little information exists on the importance of these enzymes for homeostasis of normal tissues. One study actually suggested that FTase is entirely dispensable. To explore the importance of the protein prenyltransferases for normal tissues, we used conditional knockout alleles for Fntb and Pggt1b (which encode the β-subunits of FTase and GGTase-I, respectively) and a keratin 14–Cre transgene to create mice lacking FTase or GGTase-I in skin keratinocytes. Keratinocyte-specific Fntb knockout mice were viable but developed severe alopecia. Although hair follicles appeared normal during development, they were morphologically abnormal after birth, and ultrastructural and immunohistochemical studies revealed many apoptotic cells. The interfollicular epidermis of Fntb -deficient mice appeared normal; however, keratinocytes from these mice could not proliferate in culture. As expected, non-farnesylated prelamin A and non-farnesylated DNAJA1 accumulated in Fntb -deficient keratinocytes. Keratinocyte-specific Pggt1b knockout mice survived development but died shortly after birth. Like Fntb -deficient keratinocytes, Pggt1b -deficient keratinocytes did not proliferate in culture. Thus, both FTase and GGTase-I are required for the homeostasis of skin keratinocytes.

Details

Title: Subtitle: Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes
Creators: Roger Lee - ,
Sandy Y Chang - ,
Hung Trinh - University of California
Yiping Tu - ,
Andrew C White - University of California
Brandon S.J Davies - ,
Martin O Bergo - Sahlgrenska University Hospital
Loren G Fong - ,
William E Lowry - University of California
Stephen G Young - ,
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.19(8), pp.1603-1617
DOI: 10.1093/hmg/ddq036
PMID: 20106865
PMCID: PMC2846164
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: Oxford University Press
Language: English
Date published: 04/15/2010
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
Record Identifier: 9984025287602771

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