Biology subjects

Boukhali, M.

Publications and source records attributed to Boukhali, M..

4 recordsLinked to original sources

bioRxiv2021

Ribosome changes elicit non-canonical translation for chemosurvival in G0 leukemic cells

Quiescent leukemic cells survive chemotherapy, with translation changes. Our data reveal that FXR1, a protein amplified in several aggressive cancers, increases in quiescent and chemo- treated leukemic cells, and promotes chemosurvival. This suggests undiscovered roles for this RNA- and ribosome-associated protein in chemosurvival. FXR1 depletion decreases translation and ribosome subunits, with altered rRNAs, snoRNAs, and ribosomal proteins (RPs). We find that FXR1 binds factors that promote ribosome gene transcription and bind snoRNAs. Ribosome changes increased in FXR1-overexpressing cells, including increased snoRNAs and RPLP0/uL10, activate eIF2 kinases. Accordingly, phospho-eIF2 increases, enabling non- canonical translation of survival and immune regulators in FXR1-overexpressing cells. Overriding these with inhibitors reduces chemosurvival. Thus, increased FXR1 in quiescent or chemo-treated leukemic cells, alters ribosomes that trigger stress signals to re-direct translation for chemosurvival. One Sentence SummaryFXR1 alters ribosomes in G0, which induce stress signals to elicit noncanonical translation for AML drug and immune survival.

molecular biology↗

bioRxiv2021

E2F/Dp inactivation in fat body cells triggers systemic metabolic changes

The E2F transcription factors play a critical role in controlling cell fate. In Drosophila, the inactivation of E2F in either muscle or fat body results in lethality, suggesting an essential function for E2F in these tissues. However, the cellular and organismal consequences of inactivating E2F in these tissues are not fully understood. Here, we show that the E2F loss exerts both tissue-intrinsic and systemic effects. The proteomic profiling of E2F-deficient muscle and fat body revealed that E2F regulates carbohydrate metabolism, a conclusion further supported by metabolomic profiling. Intriguingly, animals with E2F-deficient fat body had a lower level of circulating trehalose and reduced storage of fat. Strikingly, a sugar supplement was sufficient to restore both trehalose and fat levels, and subsequently, rescued animal lethality. Collectively, our data highlight the unexpected complexity of E2F mutant phenotype, which is a result of combining both tissue-specific and systemic changes that contribute to animal development.

developmental biology↗

bioRxiv2019

Quantitative proteomics reveals remodeling of protein repertoire across life phases of Daphnia pulex

The microcrustacean Daphnia is becoming an organism of choice for genomic and proteomic studies of the effects of environmental stressors. However, the changes in protein expression across the life cycle have not been fully characterized. We analyzed the proteomes of adult females, juveniles, asexually produced embryos, and the ephippia - resting stages containing two sexually produced diapausing freezing- and desiccation-resistant embryos. Overall, we were significantly more likely to detect proteins with known molecular functions than proteins with no detectable orthology. Similarly we could detect those with stronger gene model support, as judged by mutual best BLAST hits between two independent genome assemblies than those without such support. This suggests that we could apply our proteomics pipeline to verify hypothesized proteins, even given less-than-perfect reference gene models. In particular, we observed up-regulation of vitellogenins and down-regulation of actins and myosins in embryos of both types, as compared to juveniles and adults and overrepresentation of cell-cycle related proteins in the developing embryos, as compared to both diapausing embryos and adults. We found upregulation of small heat-shock proteins and redox peroxidases, as well as overrepresentation of stress-response proteins in the ephippium relative to the asexually produced non-diapausing embryos. The ephippium also showed up-regulation of three trehalose-synthesis proteins and down-regulation of a trehalose hydrolase, consistent with the role of trehalose in protection against freezing and desiccation.\n\nStatement of significance of the studyFreshwater plankton crustacean Daphnia is rapidly becoming a model organism of choice for ecological and developmental genomics. While there have been several advances towards establishing the protocols and reference datasets for proteomics, a detailed dataset covering several main steps of asexual and sexual phases of Daphnia life cycle is not yet available. Moreover, different versions of D. pulex genome differ in the number of protein-coding genes identified; it is unclear whether these differences are caused by differences between sequenced genotypes or between gene model methodology used. In this study we report LC-MS2/MS3 proteomes of whole body adult females, juvenile females, asexually produces embryos and diapausing eggs capable of surviving freezing and desiccation.

systems biology↗

bioRxiv2018

A post-transcriptional program of chemoresistance by AU-rich elements/TTP in cancer quiescence

BackgroundQuiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown.\n\nResultsWe induced chemoresistant and quiescent (G0) leukemic cells by serum-starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the up-regulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, tristetraprolin (TTP) in G0. This permits expression of ARE-bearing TNF and DUSP1 that promote chemoresistance. Conversely, inhibition of TTP phophorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNF--prior to or along with chemotherapy--substantially reduced chemoresistance in primary leukemic cells ex vivo and in vivo.\n\nConclusionsThese studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE bearing mRNAs that promote chemoresistance. By disrupting this pathway, we developed an effective combination therapy against chemosurvival.

cancer biology↗