The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia

Abstract

Oncogenes trigger replicative stress that can lead to genetic instability, which participates in cancer progression. Thus, determining how cells cope with replicative stress can help our understanding of oncogenesis and lead to the identification of new antitumor treatment targets. We previously showed that constitutive overexpression of the oncogenic transcription factor Spi1/PU.1 leads to pre-leukemic cells that have a shortened S phase duration with an increased replication fork speed and increased mutability in the absence of DNA breaks. Here, we demonstrate that the S phase checkpoint protein CHK1 is maintained in a low phosphorylation state in Spi1/PU.1-overexpressing cells and provide evidence that this is not due to negative control of its primary kinase ATR. Notably, we found that the expression of the CHK1 phosphatase PP1α is increased in Spi1/PU.1-overexpressing cells. By exogenously modulating its activity, we demonstrate that PP1α is required to maintain CHK1 in a dephosphorylated state and, more importantly, that it is responsible for the accelerated replication fork progression in Spi1/PU.1-overexpressing cells. These results identify a novel pathway by which an oncogene influences replication in the absence of DNA damage.

Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress

“…More specifically, SPI1/PU.1 is integral for the maturation of microglia, lymphocytes, and the majority of myeloid cell lines. As such, SPI1/PU.1 is critical to the maturation and regulation of the immune system and brain inflammation, two processes that are pathogenic hallmarks of TSC (59)(60)(61). Furthermore, SPI1/PU.1 has been instigated in leukemia, Alzheimer's disease and, notably in the context of epileptogenic pathologies, in the chronic transcriptional changes that result from experimental traumatic brain injury (TBI) in rats (62)(63)(64).…”

SPI1 Mediates N-Myristoyltransferase 1 to Advance Gastric Cancer Progression via PI3K/AKT/mTOR Pathway

“…As an oncogenic factor that mediates cell carcinogenesis, SPI1 plays a crucial role in the occurrence and deterioration of cancer [37,38]. When the SPI1 proto-oncogene is overactivated, a large number of transcription factors SPI1 will be expressed.…”

An Integrative Bioinformatics Analysis of the Potential Mechanisms Involved in Propofol Affecting Hippocampal Neuronal Cells

“…Inappropriate Spi1 expression is oncogenic. However, the molecular mechanisms mediating the oncogenic function of Spi1 are complex and not yet fully understood [ 21 ]. In addition, Spi1 transcription factors are important in regulating macrophage and neutrophil development [ 22 ].…”