Tumor suppressor cross-talk: The p53 and TGFβ pathways converge to repress gene transcription
A fundamental function of the tumor suppressors p53 and TGFβ is protection of cells against cellular transformation by induction of growth arrest and apoptosis. Essential components of both the p53 and TGFβ pathways are commonly targeted for mutation and/or dysfunction during tumor development. Despite performing similar functions and acting on a common subset of genes, p53 and TGFβ have been thought to operate independently of each other. Here, I provide evidence that these two tumor suppressors cooperate to repress transcription of alpha fetoprotein (AFP), a gene crucial for brain sexual differentiation. AFP transcription is robustly induced in the fetal liver and is dramatically repressed shortly after birth. This repression is disrupted in liver tumors and results in over-expression of AFP as a tumor marker. I investigated the molecular mechanisms responsible for AFP repression and its reactivation during tumorigenesis. I find, that upon receiving TGFβ stimulus, p53 and effector molecules of the TGFβ pathway, (Smad4, phophorylated Smad2 and SnoN) bind to an overlapping Smad Binding Element and p53-Response Element (SBE/p53RE) present within the AFP distal promoter. This DNA-bound repressor complex recruits a co-repressor protein, mSin3A to trigger chromatin compaction and loss of RNA Polymerase II binding at the start site of transcription. Both p53 and SnoN are required for TGFβ mediated AFP transcription repression because RNAi-mediated depletion of SnoN and/or p53 compromises this repression. p53 is essential for recruiting Smads and the co-repressor mSin3A to SBE/p53RE. TGFβ-mediated repression of AFP transcription requires a C-terminal region of p53, the same region that p53 uses to interact with Smads. Despite the fact that they have overlapping binding sites, p53 and Smads appear to be able to simultaneously assemble at the SBE/p53RE without steric hindrance, based on our structural modeling studies. These findings establish a mechanism for p53 and TGFβ cross-talk and support a model whereby p53 anchors activated Smads to mediate transcriptional regulation of tumor-associated genes.
Wilkinson, Deepti Srinivas, "Tumor suppressor cross-talk: The p53 and TGFβ pathways converge to repress gene transcription" (2007). Texas Medical Center Dissertations (via ProQuest). AAI3256566.