Abstract
P21-activated kinase 1 (PAK1), a serine/threonine protein kinase, modulates many cellular processes by phosphorylating its downstream substrates. In addition to its role in the cytoplasm, PAK1 also affects gene transcription due to its nuclear localization and association with chromatin. It is now recognized that PAK1 kinase activity and its nuclear translocation are rapidly stimulated by ionizing radiation (IR), and that PAK1 activation is a component of the DNA damage response. Owing to the role of PAK1 in the cell survival, its association with the chromatin, and now, stimulation by ionizing radiation, we hypothesize that PAK1 may be contributing to modulation of genes with roles in cellular processes that might be important in the DNA damage response. The purpose of this study was to identify new PAK1 targets in response to ionizing radiation with putative role in the DNA damage response. We examined the effect of IR on the gene expression patterns in the murine embryonic fibroblasts with or without Pak1 using microarray technology. Differentially expressed transcripts were identified using Gene Spring GX 10.0.2. Pathway, network, functional analyses and gene family classification were carried out using Kyoto Encyclopedia of Genes and Genomes (KEGG), Ingenuity Pathway, Gene Ontology and PANTHER respectively. Selective targets of PAK1 were validated by RT-qPCR. For the first time, we provide a genome-wide analysis of PAK1 and identify its targets with potential roles in the DNA damage response. Gene Ontology analysis identified genes in the IR-stimulated cells that were involved in cell cycle arrest and cell death. Pathway analysis revealed p53 pathway being most influenced by IR responsive, PAK1 targets. Gene family of transcription factors was over represented and gene networks involved in DNA replication, repair and cellular signaling were identified. In brief, this study identifies novel PAK1 dependent IR responsive genes which reveal new aspects of PAK1 biology.
Highlights
The mammalian PAK family contains six serine/threonine kinases divided into two subgroups, group I (PAK 1–3) and group II (PAK 4–6) on the basis of structural and functional similarities [1,2,3]
To identify the genes regulated by P21-activated kinase 1 (PAK1) in response to IR, the WT and PAK1 KO murine embryonic fibroblasts (MEFs) were subjected to ionizing radiation dose rate of 3.04 Gy/min at room temperature
We deduced the IR responsive gene list by various cross comparisons between genes lists obtained after analyzing wild-type (WT) and wild-type treated with IR (WT-IR) samples and WT-IR and knock-out treated by IR (KO-IR) samples
Summary
The mammalian PAK family contains six serine/threonine kinases divided into two subgroups, group I (PAK 1–3) and group II (PAK 4–6) on the basis of structural and functional similarities [1,2,3]. Members of this family share significant homology in the kinase domain , the biological functions of each member are distinct and they are dictated by the variable N-terminal regulatory domain [1,2]. PAK1 phosphorylates its downstream substrates, that are responsible for various biological effects of PAK1 kinase in cancer cells [1,3]. Increased PAK1 expression and activity have been documented in a variety of human cancers, including breast, colon, ovarian, bladder, and brain cancers [1,3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
