A Benzinger

A Brunet

A Reinacher-Schick

Abdelouahid Maghnouj

AJ Muslin

C Caulin

DH Jones

DK Trask

DM Toivola

G Rigaut

G Tzivion

GV Tolstonog

H Bühler

H Ji

H Quentmeier

HE Schaafsma

Helmut E Meyer

HY Kao

I Schwarte-Waldhoff

Irmgard Schwarte-Waldhoff

J Jin

J Kirfel

J Liao

J Zha

Johanna B Munding

JS Zhang

K Birkenkamp-Demtroder

K Marcus

K Wilhelmsen

Kai Stühler

Katrin Marcus

M Hesse

M Miyaki

M Pozuelo Rubio

MB Yaffe

MJ Calonge

ML Casanova

MS Chen

N Muller

NO Ku

P ten Dijke

PA Coulombe

R Derynck

R Moll

René Jackstadt

RJ Zarbo

S Kim

S Uchida

S Yamada

SA Hahn

SE Meek

SN Dalal

SS Margolis

Stephan A Hahn

Susanne Klein-Scory

Sven-T Liffers

T Sekimoto

Thomas Schulenborg

Ulrike Herbrand

Wolff Schmiegel

X Wang

Y Shi

Z Li

BMC Cancer

English

PubMed

Springer - Publisher Connector

Keratin 23, a novel DPC4/Smad4 target gene which binds 14-3-3ε

Abstract
          
            Background
            Inactivating mutations of SMAD4 are frequent in metastatic colorectal carcinomas. In previous analyses, we were able to show that restoration of Smad4 expression in Smad4-deficient SW480 human colon carcinoma cells was adequate to suppress tumorigenicity and invasive potential, whereas in vitro cell growth was not affected. Using this cellular model system, we searched for new Smad4 targets comparing nuclear subproteomes derived from Smad4 re-expressing and Smad4 negative SW480 cells.
          
          
            Methods
            High resolution two-dimensional (2D) gel electrophoresis was applied to identify novel Smad4 targets in the nuclear subproteome of Smad4 re-expressing SW480 cells. The identified candidate protein Keratin 23 was further characterized by tandem affinity purification. Immunoprecipitation, subfractionation and immunolocalization studies in combination with RNAi were used to validate the Keratin 23-14-3-3ε interaction.
          
          
            Results
            We identified keratins 8 and 18, heat shock proteins 60 and 70, plectin 1, as well as 14-3-3ε and γ as novel proteins present in the KRT23-interacting complex. Co-immunoprecipitation and subfractionation analyses as well as immunolocalization studies in our Smad4-SW480 model cells provided further evidence that KRT23 associates with 14-3-3ε and that Smad4 dependent KRT23 up-regulation induces a shift of the 14-3-3ε protein from a nuclear to a cytoplasmic localization.
          
          
            Conclusion
            Based on our findings we propose a new regulatory circuitry involving Smad4 dependent up-regulation of KRT23 (directly or indirectly) which in turn modulates the interaction between KRT23 and 14-3-3ε leading to a cytoplasmic sequestration of 14-3-3ε. This cytoplasmic KRT23-14-3-3 interaction may alter the functional status of the well described 14-3-3 scaffold protein, known to regulate key cellular processes, such as signal transduction, cell cycle control, and apoptosis and may thus be a previously unappreciated facet of the Smad4 tumor suppressive circuitry.
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Keratin 23, a novel DPC4/Smad4 target gene which binds 14-3-3ε

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