Identification of Tcf-4 as a transcriptional target of p53 signalling.
T-cell factor (Tcf)-4 is a main transcription factor to pass on Wnt/beta-catenin signalling. The tumour suppressor protein p53 contributes as a transcription factor to cell-cycle arrest and apoptosis induction. Mutations of components in p53 and Wnt/beta-catenin signalling networks play a part in tumour formation. Here, we identify the Tcf-4 gene as a downstream effector of p53. Induction of wild-type p53 in a tet-off regulated human colon cell system leads to the reduction of Tcf-4 mRNA and protein levels. Also, mRNA of the Tcf-4 target gene uPAR is downregulated after p53 induction. Expression of a luciferase reporter controlled by the Tcf-4 promoter is repressed by wild-type p53, but not by a p53 mutant deficient in DNA binding. Such a regulation is seen in cell lines of different origin. These findings directly link Wnt/beta-catenin signalling and p53 tumour suppressor function and may provide a mechanism by which loss of p53 function contributes to progression in the adenoma/carcinoma sequence in colon tumours. Furthermore, since Tcf-4 is expressed in many tissues and downregulation of Tcf-4 by p53 is seen in several different cell types, this regulation likely plays a role in proliferation control of all tissues that can express p53 and Tcf-4.
Medizinische Klinik und Poliklinik II, Max-Bürger-Forschungszentrum, Universität Leipzig, Johannisallee 30, Leipzig D-04103, Germany.
Karen
K
Rother
Cindy
C
Johne
Katja
K
Spiesbach
Ulrike
U
Haugwitz
Katrin
K
Tschöp
Mark
M
Wasner
Ludger
L
Klein-Hitpass
Tarik
T
Möröy
Joachim
J
Mössner
Kurt
K
Engeland
D000818:Animals; D003598:Cytoskeletal Proteins / Q000502:physiology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000502:physiology; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin