• Something wrong with this record ?

CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling

V. Danek, J. Tureckova, K. Huebner, K. Erlenbach-Wuensch, P. Baranova, J. Dobes, J. Balounova, M. Simova, V. Novosadova, CE. Madureira Trufen, M. Prochazkova, P. Talacko, K. Harant, C. Barinka, IM. Beck, R. Schneider-Stock, R. Sedlacek, J. Prochazka

. 2025 ; 621 (-) : 217663. [pub] 20250320

Language English Country Ireland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25015216

Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc25015216
003      
CZ-PrNML
005      
20250731090835.0
007      
ta
008      
250708e20250320ie f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.canlet.2025.217663 $2 doi
035    __
$a (PubMed)40120800
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a ie
100    1_
$a Danek, Veronika $u Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
245    10
$a CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling / $c V. Danek, J. Tureckova, K. Huebner, K. Erlenbach-Wuensch, P. Baranova, J. Dobes, J. Balounova, M. Simova, V. Novosadova, CE. Madureira Trufen, M. Prochazkova, P. Talacko, K. Harant, C. Barinka, IM. Beck, R. Schneider-Stock, R. Sedlacek, J. Prochazka
520    9_
$a Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.
650    12
$a protein Smad3 $x metabolismus $x genetika $7 D051900
650    _2
$a lidé $7 D006801
650    12
$a kulinové proteiny $x metabolismus $x genetika $7 D044842
650    12
$a ubikvitinligasy $x metabolismus $x genetika $7 D044767
650    12
$a nádorové supresorové proteiny $x metabolismus $x genetika $7 D025521
650    12
$a kolorektální nádory $x patologie $x genetika $x metabolismus $7 D015179
650    _2
$a zvířata $7 D000818
650    _2
$a ubikvitinace $7 D054875
650    _2
$a signální dráha Wnt $7 D060449
650    _2
$a myši $7 D051379
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a HCT116 buňky $7 D045325
650    _2
$a regulace genové exprese u nádorů $7 D015972
655    _2
$a časopisecké články $7 D016428
700    1_
$a Tureckova, Jolana $u Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Huebner, Kerstin $u Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
700    1_
$a Erlenbach-Wuensch, Katharina $u Institute of Pathology, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany
700    1_
$a Baranova, Petra $u Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, 252 50, Czech Republic
700    1_
$a Dobes, Jan $u Department of Cell Biology, Faculty of Science, Charles University, 128 00, Prague, Czech Republic
700    1_
$a Balounova, Jana $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Simova, Michaela $u Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Novosadova, Vendula $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Madureira Trufen, Carlos Eduardo $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Prochazkova, Michaela $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Talacko, Pavel $u BIOCEV Proteomics Core Facility, Faculty of Science, Charles University, Vestec, 252 50, Czech Republic
700    1_
$a Harant, Karel $u BIOCEV Proteomics Core Facility, Faculty of Science, Charles University, Vestec, 252 50, Czech Republic
700    1_
$a Barinka, Cyril $u Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, 252 50, Czech Republic
700    1_
$a Beck, Inken M $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Animal Research Centre, Ulm University, Ulm, Germany
700    1_
$a Schneider-Stock, Regine $u Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany; Institute of Pathology, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany
700    1_
$a Sedlacek, Radislav $u Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
700    1_
$a Prochazka, Jan $u Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic. Electronic address: jan.prochazka@img.cas.cz
773    0_
$w MED00001044 $t Cancer letters $x 1872-7980 $g Roč. 621 (20250320), s. 217663
856    41
$u https://pubmed.ncbi.nlm.nih.gov/40120800 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20250708 $b ABA008
991    __
$a 20250731090830 $b ABA008
999    __
$a ok $b bmc $g 2366209 $s 1252341
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2025 $b 621 $c - $d 217663 $e 20250320 $i 1872-7980 $m Cancer letters $n Cancer Lett $x MED00001044
LZP    __
$a Pubmed-20250708
Back

Find record

Citation metrics

Archiving options