Nucleolar targets of chemotherapy involved in cell cycle and growth control

Target genes of the onco-protein Myc coordinate cell growth and proliferation. Myc target genes with nucleolar functions play a central role in ribosome biogenesis, a cellular process, which is also required for destabilization of the tumor suppressor protein p53 in proliferating cells. Aim of the project is to unravel the molecular mechanisms and signaling pathways leading to p53 stabilization after inhibition of ribosome biogenesis.

Previously we have identified and characterized the c-myc target genes pes1, bop1, and wdr12. Their products form a trimeric complex, PeBoW, which is essential for processing of ribosomal RNA. Knockdown of PeBoW-components or other ribosome biogenesis factors consistently induce a stabilization of p53 and cell cycle arrest. We could now show that a large number of chemotherapeutic drugs inhibit ribosome biogenesis either at the level of rRNA transcription, or at the levels of early or late rRNA processing. These and other observations led to the current model that functional ribosome biogenesis is a prerequisite for destabilization of p53 in proliferating cells.

Figure: MEG
Fig.: MEG

Functional analysis of the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II

In higher eukaryotes, an unusual carboxy-terminal domain (CTD) is crucial to the function of RNA polymerase II in transcription. The CTD consists of multiple heptapeptide repeats with the consensus repeat tyr1-ser2-pro3-thr4-ser5-pro6-ser7. Specific post-translational modifications in CTD appear to fulfil specific tasks during the transcription process.  A model emerges in which modifications in histone tails of chromatin are involved in the recruitment of CTD modifying enzymes and vice versa. This might imply that CTD has co-evolved with chromatin, and that epigenetic information in form of modified chromatin could form a blueprint, as how to transcribe, splice and mature mRNA. Inversely, CTD might also be involved in the transformation of cellular signals into epigenetic information. In this context, enzymatic modification of CTD residues plays a central role. While phosphorylation of ser2, ser5, and ser7 is now well established, little or nothing is known about the modification of tyr1 and thr4 residues in CTD. Recent evidence from our laboratory indicates that both these residues are also phosphorylated in vivo.

Figure: MEG
Fig.: MEG

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