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Publication
The role of Rac1-modulated gene transcription in tumorigenesis
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Authors
Advisor(s)
Abstract(s)
Gene expression regulation is a dynamic and multi-step process,
in which transcription plays a major role. Transcription initiation depends
on binding of transcription regulators to DNA elements located in promoter
or enhancer regions, a process often controlled by signalling pathways.
One such pathway is regulated by Rac1, a member of the Rho family of
small GTPases involved in cell proliferation, adhesion and migration. In
this work, novel links between Rac1 signalling and transcriptional
regulation in colorectal tumour cells are described. First, it is shown that
Rac1 activation leads to PAK1-mediated phosphorylation of the
transcriptional repressor BCL-6 in colorectal cancer cells, inactivating its
repressor function. In the presence of active Rac1, BCL-6 redistribution
within the nucleus, a reduction in its affinity to chromatin and increased
expression of the endogenous target genes NFKB1 and CD44, and of a
BCL-6-controlled luciferase reporter construct were observed. Next, it was
found that Rac1 signalling promotes gene transcription by inducing a
transcriptional switch from the repressor BCL-6 to the activator STAT5A at
the promoter of certain target genes. Using chromatin
immunoprecipitation, it is demonstrated in different colorectal cell lines
that active Rac1 promotes release of BCL-6 with concomitant nuclear
translocation and binding of STAT5A at the same promoter site. Three
endogenous cell-cycle-related genes (CCND2, CDKN2B, SUMO1) were
identified to be inversely regulated by BCL-6 and STAT5A and shown to
respond to Rac1 signalling with promoter occupancy switches that
correlate directly with changes in their expression levels.
This work provides new mechanistic insights into how Rac1
signalling modulates gene transcription through the switching between transcription factors and contributes to uncovering the implications of
deregulated Rac1 activity in cancer.
Description
Tese de Doutoramento em Biologia (Biologia Molecular) apresentada ao Instituto de Tecnologia Química e Biológica da Universidade Nova de Lisboa, 2012.
Keywords
Vias de Transdução de Sinal e Patologias Associadas Rac1 Colorectal Cancer Gene Expression Transcription Regulation STAT5 BCL-6