Forkhead box transcription factor, FOXM1 is implicated in several cellular processes such as proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, ...angiogenesis, apoptosis, and redox signaling. In addition to being a boon for the normal functioning of a cell, FOXM1 turns out to be a bane by manifesting in several disease scenarios including cancer. It has been given an oncogenic status based on several evidences indicating its role in tumor development and progression. FOXM1 is highly expressed in several cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in angiogenesis, invasion, migration, self- renewal and drug resistance. In this review, we attempt to understand various mechanisms underlying FOXM1 gene and protein regulation in cancer including the different signaling pathways, post-transcriptional and post-translational modifications. Identifying crucial molecules associated with these processes can aid in the development of potential pharmacological approaches to curb FOXM1 mediated tumorigenesis.
Mutations in p53 gene are one of the hallmarks of tumor development. Specific targeting of mutant p53 protein has a promising role in cancer therapeutics. Our preliminary observation showed ...destabilization of mutant p53 protein in SW480, MiaPaCa and MDAMB231 cell lines upon thiostrepton treatment. In order to elucidate the mechanism of thiostrepton triggered mutant p53 degradation, we explored the impact of proteasome inhibition on activation of autophagy. Combined treatment of thiostrepton and cycloheximide/chloroquine prevented the degradation of mutant p53 protein, reinforcing autophagy as the means of mutant p53 destabilization. Our initial studies suggested that mutant p53 degradation post THSP treatment was carried out by BAG3 mediated autophagy, based on the evidence of BAG1 to BAG3 switching. Subsequent interactome analysis performed post thiostrepton treatment revealed an association of p53 with autophagosome complex associated proteins such as BAG3, p62 and HSC70. Reaccumulation of p53 was seen in BAG3 silenced cells treated with thiostrepton, thereby confirming the role of BAG3 in destabilization of this molecule. Further, localization of p53 into the lysosome upon THSP treatment substantiated our findings that mutant p53 was degraded by an autopahgic process.
Thiostrepton degrades mutant p53 by eliciting an autophagic response in SW480 cells. This autophagic process was suggested to be mediated by BAG3 protein.
The discovery of a potent gene regulating tumorigenesis and drug resistance is of high clinical importance.
STIL
is an oncogene; however, its molecular associations and role in colorectal oncogenesis ...are unknown. In this study, we have explored the role of
STIL
gene in tumorigenesis and studied its molecular targets in colorectal cancer (CRC).
STIL
silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers
CD133
and
CD44
and drug resistant markers
thymidylate synthase
,
ABCB1
, and
ABCG2
both in
in-vitro
and
in-vivo
CRC models. In addition, high expression of
STIL
mRNA was found to be associated with reduced disease-free survival in CRC cases. Interestingly, we observed that
STIL
-mediated regulation of stemness and drug resistant genes is not exclusively governed by Sonic hedgehog (Shh) signaling. Remarkably, we found
STIL
regulate β-catenin levels through p-AKT, independent of Shh pathway. This partially answers Shh independent regulatory mechanism of cancer stem cell (CSC) markers by
STIL
. Our study suggests an instrumental role of
STIL
in molecular manifestation of CRC and progression.
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•Cd disrupts structural integrity of heart leading to cardiac hypertrophic remodelling.•Cd elevates cardiac marker enzymes and lipid levels in blood.•GA enhances antioxidant activity ...& decreases the expression of hypertrophy markers.•GA inhibits Cd mediated hypertrophy by regulating Nrf2 and PECAM-1 signalling pathway.
Gallic acid (GA) is an abundant natural polyphenolic compound found in vegetable and fruits that reduces the cardiac disease risk factor. This study aims to evaluate GA's role on cadmium (Cd) induced cardiac remodelling in experimental rats. Male Wistar rats were exposed to Cd (15 ppm) in drinking water and administered with GA orally (15 mg/kg/d) for 60 days. The results showed that GA regulated the lipid profile and reduced the LDL to 57 % compared with Cd treated rats. GA inhibited cardiac marker enzymes activity of CK-NAC (to 72.7 %) and CK-MB (to 100.3 %). Moreover, GA attenuated lipid peroxidation and enhanced the cardiac glutathione S transferase (GST) activity (89.2 %), glutathione peroxidase (GPx) (87 %), superoxide dismutase (SOD) (88.4 %) and catalase (CAT) activity (86.5 %). Histopathological examination showed that GA impaired the ventricular hypertrophy and fibrotic proliferation induced by Cd in rats. The combination of GA + Cd, decreased the gene expression of ANP (1-fold), BNP (0.5-fold) and β- MHC (0.9-fold). Furthermore, GA significantly reduced the expression of profibrotic (TGF-β) and proinflammatory (MCP-1) gene in Cd intoxicated rats. GA upregulated the expression of Nrf2 (2-fold), HO-1 (3-fold), and PECAM-1 (0.6-fold), which augments the detoxifying enzyme activity and cellular immunity in Cd intoxicated rats. The increased protein expression of Nrf2, PECAM-1 and decreased AKT-1 levels confirmed the mechanical action of GA during the hypertrophic condition. Thus, our results suggest that GA could act as a potential therapeutic agent regulating Nrf2 and PECAM-1 signalling pathways, thereby ameliorating Cd-induced pathological cardiac remodelling.
The altered molecular pathways in response to chemotherapeutic interventions impose limitations on breast cancer treatments. Therefore, understanding the outcome of these alternative pathways may ...help in improving the chemotherapy. In this study, using hormone responsive and hormone independent breast cancer cells, MCF-7 and MDAMB-231 respectively, we studied some of the molecular pathways that contribute to cancer progression. Since the cancer chaperone, Hsp90 inhibitors have entered the clinical trials, we used Hsp90 inhibitor, 17AAG to examine the outcome of altered molecular pathways. The observed differential sensitivity in MCF7 and MDAMB-231 cells to 17AAG treatment is then attributed to both tumor microenvironment mediated by hypoxia and acquired alterations in the endogenous stem cell pool. Interestingly, tumor cells are able to retain epithelial characteristics in addition to gaining mesenchymal characteristics in response to 17AAG treatment. We observed MCF-7 cells exhibiting induced cellular differentiation, whereas MDAMB-231 cells exhibiting reduced cellular differentiation in response to 17AAG treatment. These changes are subsequently found to be the sporadic outcome of altered epigenetic landscape. The mice tumor xenograft studies have revealed that decreased metastatic potential of MCF-7 and increased metastatic potential with altered homing properties of MDAMB-231 are the outcome of altered molecular pathways. Our findings expose the interference of altered molecular pathways influencing the therapeutic outcome.
The ability of tumor cells to alter their phenotype especially during chemotherapeutic interventions challenges the treatment response. Tumor cells exhibit altered molecular signatures in response to chemotherapeutic interventions. While the tumor microenvironment influence the patterns of molecular signatures, HSp90 inhibition altered the epigenetic landscape leading to cellular heterogeneity and thus contributes to altered cellular tropism. Altered cellular tropism, therefore, challenges the treatment response and develops into aggressive cancer. Display omitted
•Breast cancer cells exhibit differential sensitivity to Hsp90 inhibition.•Chemotherapeutic stimulation triggers the stem-like cell transition in breast cancer cells.•Altered molecular signatures in response to hypoxia decides the therapeutic outcome.•Altered molecular signatures alters the homing property of breast cancer cells.•Hsp90 inhibitors in combination with hypoxia interferes with the metastatic potential of breast cancer cells.
Heat shock instantly reprograms transcription. Whether gene and enhancer transcription fully recover from stress and whether stress establishes a memory by provoking transcription regulation that ...persists through mitosis remained unknown. Here, we measured nascent transcription and chromatin accessibility in unconditioned cells and in the daughters of stress-exposed cells. Tracking transcription genome-wide at nucleotide-resolution revealed that cells precisely restored RNA polymerase II (Pol II) distribution at gene bodies and enhancers upon recovery from stress. However, a single heat exposure in embryonic fibroblasts primed a faster gene induction in their daughter cells by increasing promoter-proximal Pol II pausing and by accelerating the pause release. In K562 erythroleukemia cells, repeated stress refined basal and heat-induced transcription over mitotic division and decelerated termination-coupled pre-mRNA processing. The slower termination retained transcripts on the chromatin and reduced recycling of Pol II. These results demonstrate that heat-induced transcriptional memory acts through promoter-proximal pause release and pre-mRNA processing at transcription termination.
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•Cell-type-specific transcription precisely recovers after heat shock•Daughters of stressed cells accelerate heat induction of quality control genes•Daughters of repeatedly stressed cells refine basal and inducible transcription•Transcriptional memory acts at Pol II pause release and transcription termination
Heat shock reprograms transcription at genes and enhancers. Vihervaara et al. reveal that cells precisely restore transcription program after heat exposure and that cells establish a transcriptional memory of stress. In the daughters of stressed cells, increased Pol II pause release accelerates gene activation and reduced transcription termination decelerates mRNA processing.
RNA Polymerase II (Pol II) is a multi-subunit complex that undergoes covalent modifications as transcription proceeds through genes and enhancers. Rate-limiting steps of transcription control Pol II ...recruitment, site and degree of initiation, pausing duration, productive elongation, nascent transcript processing, transcription termination, and Pol II recycling. Here, we develop Precision Run-On coupled to Immuno-Precipitation sequencing (PRO-IP-seq), which double-selects nascent RNAs and transcription complexes, and track phosphorylation of Pol II C-terminal domain (CTD) at nucleotide-resolution. We uncover precise positional control of Pol II CTD phosphorylation as transcription proceeds from the initiating nucleotide (+1 nt), through early (+18 to +30 nt) and late (+31 to +60 nt) promoter-proximal pause, and into productive elongation. Pol II CTD is predominantly unphosphorylated from initiation until the early pause-region, whereas serine-2- and serine-5-phosphorylations are preferentially deposited in the later pause-region. Upon pause-release, serine-7-phosphorylation rapidly increases and dominates over the region where Pol II assembles elongation factors and accelerates to its full elongational speed. Interestingly, tracking CTD modifications upon heat-induced transcriptional reprogramming demonstrates that Pol II with phosphorylated CTD remains paused on thousands of heat-repressed genes. These results uncover dynamic Pol II regulation at rate-limiting steps of transcription and provide a nucleotide-resolution technique for tracking composition of engaged transcription complexes.
Healthy ageing has disparate effects on different cognitive domains. The neural basis of these differences, however, is largely unknown. We investigated this question by using Independent Components ...Analysis to obtain functional brain components from 98 healthy participants aged 23-87 years from the population-based Cam-CAN cohort. Participants performed two cognitive tasks that show age-related decrease (fluid intelligence and object naming) and a syntactic comprehension task that shows age-related preservation. We report that activation of task-positive neural components predicts inter-individual differences in performance in each task across the adult lifespan. Furthermore, only the two tasks that show performance declines with age show age-related decreases in task-positive activation of neural components and decreasing default mode (DM) suppression. Our results suggest that distributed, multi-component brain responsivity supports cognition across the adult lifespan, and the maintenance of this, along with maintained DM deactivation, characterizes successful ageing and may explain differential ageing trajectories across cognitive domains.
Antigen receptor signalling activates the canonical NF-κB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 ...cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-κB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1(mut/mut) patient with healthy MALT1(+/mut) family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-κB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κB pathway-first promoting activation via the CBM--then triggering HOIL1-dependent negative-feedback termination, preventing reactivation.
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