Interplay between poxviruses and the cellular ubiquitin/ubiquitin-like pathways

Post-translational polypeptide tagging by conjugation with ubiquitin and ubiquitin-like (Ub/Ubl) molecules is a potent way to alter protein functions and/or sort specific protein targets to the proteasome for degradation. Many poxviruses interfere with the host Ub/Ubl system by encoding viral proteins that can usurp this pathway. Some of these include viral proteins of the membrane-associated RING-CH (MARCH) domain, p28/Really Interesting New Gene (RING) finger, ankyrin-repeat/F-box and Broad-complex, Tramtrack and Bric-a-Brac (BTB)/Kelch subgroups of the E3 Ub ligase superfamily. Here we describe and discuss the various strategies used by poxviruses to target and subvert the host cell Ub/Ubl systems.     

Interplay between Fanconi anemia and homologous recombination pathways in genome integrity

The Fanconi anemia (FA) pathway plays a central role in the repair of DNA interstrand crosslinks (ICLs) and regulates cellular responses to replication stress. Homologous recombination (HR), the error‐free pathway for double‐strand break (DSB) repair, is required during physiological cell cycle progression for the repair of replication‐associated DNA damage and protection of stalled replication forks. Substantial crosstalk between the two pathways has recently been unravelled, in that key HR proteins such as the RAD51 recombinase and the tumour suppressors BRCA1 and BRCA2 also play important roles in ICL repair. Consistent with this, rare patient mutations in these HR genes cause FA pathologies and have been assigned FA complementation groups. Here, we focus on the clinical and mechanistic implications of the connection between these two cancer susceptibility syndromes and on how these two molecular pathways of DNA replication and repair interact functionally to prevent genomic instability.     

Interplay between HTRA1 and classical signalling pathways in organogenesis and diseases

The high temperature requirement factor A1 (HTRA1) is a serine protease which modulates an array of signalling pathways driving basal biological processes. HTRA1 plays a significant role in cell proliferation, migration and fate determination, in addition to controlling protein aggregates through refolding, translocation or degradation. The mutation of HTRA1 has been implicated in a plethora of disorders and this has also led to its growing interest as drug therapy target. This review details the involvement of HTRA1 in certain signalling pathways, namely the transforming growth factor beta (TGF-β), canonical Wingless/Integrated (WNT) and NOTCH signalling pathways during organogenesis and various disease pathogenesis such as preeclampsia, age-related macular degeneration (AMD), small vessel disease and cancer. We have also explored possible avenues of exploiting the serine proteases for therapeutic management of these disorders.     

Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma

mTOR complex 1 (mTORC1) is implicated in cell growth control and is extensively regulated. We previously reported that in response to hypoxia, mTORC1 is inhibited by the protein regulated in development and DNA damage response 1 (REDD1). REDD1 is upregulated by hypoxia-inducible factor (HIF)-1, and forced REDD1 expression is sufficient to inhibit mTORC1. REDD1-induced mTORC1 inhibition is dependent on a protein complex formed by the tuberous sclerosis complex (TSC)1 and 2 (TSC2) proteins. In clear-cell renal cell carcinoma (ccRCC), the von Hippel-Lindau (VHL) gene is frequently inactivated leading to constitutive activation of HIF-2 and/or HIF-1, which may be expected to upregulate REDD1 and inhibit mTORC1. However, mTORC1 is frequently activated in ccRCC, and mTORC1 inhibitors are effective against this tumor type; a paradox herein examined. REDD1 was upregulated in VHL-deficient ccRCC by in silico microarray analyses, as well as by quantitative real-time PCR, Western blot, and immunohistochemistry. Vhl disruption in a mouse model was sufficient to induce Redd1. Using ccRCC-derived cell lines, we show that REDD1 upregulation in tumors is VHL dependent and that both HIF-1 and HIF-2 are, in a cell-type-dependent manner, recruited to, and essential for, REDD1 induction. Interestingly, whereas mTORC1 is responsive to REDD1 in some tumors, strategies have evolved in others, such as mutations disrupting TSC1, to subvert mTORC1 inhibition by REDD1. Sequencing analyses of 77 ccRCCs for mutations in TSC1, TSC2, and REDD1, using PTEN as a reference, implicate the TSC1 gene, and possibly REDD1, as tumor suppressors in sporadic ccRCC. Understanding how ccRCCs become refractory to REDD1-induced mTORC1 inhibition should shed light into the development of ccRCC and may aid in patient selection for molecular-targeted therapies.     

Interplay between the RNA binding‐protein Musashi and developmental signaling pathways

Musashi comprises an evolutionarily conserved family of RNA‐binding proteins (RBP) that regulate cell fate decisions during embryonic development and play key roles in the maintenance of self‐renewal and differentiation of stem cells and adult tissues. More recently, several studies have shown that any dysregulation of MSI1 and MSI2 can lead to cellular dysfunctions promoting tissue instability and tumorigenesis. Moreover, several reports have characterized many molecular interactions between members of the Musashi family with ligands and receptors of the signaling pathways responsible for controlling normal embryonic development: Notch, Transforming Growth Factor Beta (TGF‐β), Wingless (Wnt) and Hedgehog Signaling (Hh); all of which, when altered, are strongly associated with cancer onset and progression, especially in pediatric tumors. In this context, the present review aims to compile possible cross‐talks between Musashi proteins and members of the above cited molecular pathways for which dysregulation plays important roles during carcinogenesis and may be modulated by these RBP.     

Interplay between apoptotic and autophagy pathways after exposure to cerium dioxide nanoparticles in human monocytes

Engineered nanomaterials, defined as having at least one dimension smaller than 100 nm, have revolutionized many technology sectors ranging from therapeutics and diagnostics to environmental monitoring and remediation. This has resulted in a rapid increase in their manufacture over the past few years, accompanied by an increased human exposure potential. However, understanding of the interactions of nanomaterials with biological systems is still rudimentary. We have described that an environmentally and medically relevant nano metal (cerium dioxide) can affect primary human monocyte viability and interact with programmed cell death pathways leading to apoptosis and autophagic cell death. Cerium dioxide nanoparticles (CeO₂ NPs)-induced autophagy acts as a prodeath mechanism and leads to increased cytotoxicity of human monocytes. A better understanding of the implication and biological significance of CeO₂ NPs-induced autophagy and apoptosis will help us understand the risks associated with its uses and develop safer nanomedicine.     

Interplay between PI3K/Akt and MAPK signaling pathways in DNA-damaging drug-induced apoptosis

In order to elucidate the role of the mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, as well as the survival-associated PI3K/Akt signaling pathway, in the response to chemotherapy, we have conducted a comparative study regarding the effects of doxorubicin on these pathways. Doxorubicin was determined to elicit the apoptosis of NIH3T3 cells in a dose-dependent manner. Prior to cell death, both Akt and p38 MAPK were transiently activated, and subsequently inactivated almost wholly, whereas ERK and JNK evidenced sustained activations in response to the drug treatment. The inhibition of PI3K/Akt and p38 MAPK both accelerated and enhanced doxorubicin-induced apoptosis and ERK inhibition apparently exerted negative effect on apoptosis. The modulation of PI3K/Akt activation by treatment of LY294002 or expression of Akt mutants such as Akt-DN or Myr-Akt exerted a significant effect on the activation of ERK1/2. We also observed that PI3K/Akt and sustained ERK activation were associated intimately with the etoposide-induced apoptosis. Taken together, our results clearly suggest that the differential regulation of the PI3K/Akt, ERK1/2, and p38 MAPK signaling pathways are crucial in the context of DNA-damaging drug-induced apoptosis, and this has compelled us to propose that the sustained activation of ERK1/2 pathway may be generally involved in the apoptosis induced by anticancer DNA-damaging drugs, including doxorubicin and etoposide.     

Invited review: Interplay between molecular chaperones and signaling pathways in survival of heat shock.

Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.     

Interplay between inflammation and cancer

Tumor-promoting inflammation is one of the hallmarks of cancer. It has been shown that cancer development is strongly influenced by both chronic and acute inflammation process. Progress in research on inflammation revealed a connection between inflammatory processes and neoplastic transformation, the progression of tumour, and the development of metastases and recurrences. Moreover, the tumour invasive procedures (both surgery and biopsy) affect the remaining tumour cells by increasing their survival, proliferation and migration. One of the concepts explaining this phenomena is an induction of a wound healing response. While in normal tissue it is necessary for tissue repair, in tumour tissue, induction of adaptive and innate immune response related to wound healing, stimulates tumour cell survival, angiogenesis and extravasation of circulating tumour cells. It has become evident that certain types of immune response and immune cells can promote tumour progression more than others. In this review, we focus on current knowledge on carcinogenesis and promotion of cancer growth induced by inflammatory processes.     

Interaction between the light quality and flowering time pathways in Arabidopsis

Flowering in Arabidopsis is accelerated by a reduced ratio of red light to far-red light (R/FR), which indicates the proximity of competitive vegetation. By exploiting the natural genetic variation in flowering time responses to low R/FR, we obtained further insight into the complex pathways that fine-tune the transition to flowering in Arabidopsis. The Bla-6 ecotype does not flower significantly earlier in response to low R/FR, but is still able to display other features of shade avoidance, suggesting branching of low R/FR signalling. Here we show that the muted flowering response of Bla-6 is due to high levels of the floral repressor FLOWERING LOCUS C (FLC), conferred by a combination of functional FLC and FRIGIDA ( FRI ) alleles with a 'weak' FY allele. The Bla-6 FY allele encodes a protein with a corrupted WW binding domain, and we provide evidence that this locus plays a key role in the natural variation in light quality-induced flowering in Arabidopsis. In Bla-6, FLC blocks promotion to flowering by reduced R/FR by inhibiting expression of the floral integrator FLOWERING LOCUS T ( FT ) in a dose-dependent manner. Reduction of FLC removes this obstruction, and Bla6 plants then exhibit strong induction of FT and flower early in response to a low R/FR signal. This paper illustrates the intricate interaction of environmental signals and genetic factors to regulate flowering in Arabidopsis.     

Interplay of signaling pathways in plant disease resistance

Plants are under constant threat of infection by pathogens armed with a diverse array of effector molecules to colonize their host. Plants have, in turn, evolved sophisticated detection and response systems that decipher pathogen signals and induce appropriate defenses. Genetic analysis of plant mutants impaired in mounting a resistance response to invading pathogens has uncovered a number of distinct, but interconnecting, signaling networks that are under both positive and negative control. These pathways operate, at least partly, through the action of small signaling molecules such as salicylate, jasmonate and ethylene. The interplay of signals probably allows the plant to fine-tune defense responses in both local and systemic tissue.     

Cysteinesulfonate and beta-sulfopyruvate metabolism. Partitioning between decarboxylation, transamination, and reduction pathways

L-Cysteinesulfonate (L-cysteate) is present in plasma, urine, and tissues in concentrations comparable to that of L-cysteinesulfinate, the primary oxidative metabolite of L-cysteine. Although cysteinesulfonate is known to be decarboxylated to taurine by cysteinesulfinate decarboxylase, the occurrence and importance of other metabolisms has not been examined. The present studies indicate that cysteinesulfonate partitions in vivo between decarboxylation and transamination; the latter reaction is catalyzed by aspartate aminotransferase and yields beta-sulfopyruvate. Whereas beta-sulfinylpyruvate, the product of cysteinesulfinate transamination, decomposes spontaneously, beta-sulfopyruvate is stable and is reduced by malate dehydrogenase to beta-sulfolactate. When L-[1-14C]cysteinesulfonate is given to mice, 60-75% is decarboxylated to taurine and about 25% is excreted in the urine as beta-sulfolactate. beta-Sulfo[1-14C] pyruvate is found to partition about equally between beta-sulfolactate and cysteinesulfonate formation; greater than 90% of the latter is decarboxylated. Parenterally administered beta-sulfo[1-14C]lactate is mostly excreted in the urine, but 12% is metabolized via beta-sulfopyruvate and cysteinesulfonate to 14CO2 and taurine. beta-Sulfopyruvate is not excreted, and only traces of sulfoacetate, perhaps formed by oxidative decarboxylation, are detected. These studies establish that cysteinesulfonate, beta-sulfopyruvate, and beta-sulfolactate are reversibly interconverted in vivo. Since only cysteinesulfonate is directly metabolized to CO2, the rate of 14CO2 formation from L-[1-14C]cysteinesulfonate is a valid measure of total cysteinesulfinate decarboxylase activity in vivo; use of this assay permits inhibitor effects to be accurately determined in intact mice. Thus, whereas in vitro assays indicate that beta-methyleneaspartate inhibits brain, liver, and kidney cysteinesulfinate decarboxylase by 0, greater than 60, and 90%, respectively, in vivo studies with L-[1-14C]cysteinesulfonate show net metabolic inhibition is about 40%.     

Interplay between viruses and host mRNA degradation

Messenger RNA degradation is a fundamental cellular process that plays a critical role in regulating gene expression by controlling both the quality and the abundance of mRNAs in cells. Naturally, viruses must successfully interface with the robust cellular RNA degradation machinery to achieve an optimal balance between viral and cellular gene expression and establish a productive infection in the host. In the past several years, studies have discovered many elegant strategies that viruses have evolved to circumvent the cellular RNA degradation machinery, ranging from disarming the RNA decay pathways and co-opting the factors governing cellular mRNA stability to promoting host mRNA degradation that facilitates selective viral gene expression and alters the dynamics of host–pathogen interaction. This review summarizes the current knowledge of the multifaceted interaction between viruses and cellular mRNA degradation machinery to provide an insight into the regulatory mechanisms that influence gene expression in viral infections. This article is part of a Special Issue entitled: RNA Decay mechanisms.     

Interplay between endogenous and exogenous human retroviruses

In humans, retroviruses thrive more as symbionts than as parasites. Apart from the only two modern exogenous human retroviruses (human T-cell lymphotropic and immunodeficiency viruses; HTLV and HIV, respectively), ~8% of the human genome is occupied by ancient retroviral DNA [human endogenous retroviruses (HERVs)]. Here, we review the recent discoveries about the interactions between the two groups, the impact of infection by exogenous retroviruses on the expression of HERVs, the effect of HERVs on the pathogenicity of HIV and HTLV and on the severity of the diseases caused by them, and the antiviral protection that HERVs can allegedly provide to the host. Tracing the crosstalk between contemporary retroviruses and their endogenized ancestors will provide better understanding of the retroviral world.     

Interplay between MAMP-triggered and SA-mediated defense responses

Plants respond to pathogen infection using an innate immune system with at least two distinct recognition mechanisms. One mechanism recognizes microbe-associated molecular patterns (MAMPs). The other is based on resistance (R) genes and specifically recognizes certain pathogen virulence factors, including those delivered through the type III secretion system (TTSS) of bacteria. Salicylic acid (SA)-mediated responses are an important part of the R gene-mediated defense. Substantial overlaps between MAMP-triggered and SA-mediated responses have been reported. However, interactions between MAMP-triggered and SA-mediated signaling mechanisms have not been well documented. Here we report intimate interactions between MAMP-triggered and SA-mediated signaling. We found that SA accumulated at a higher level 6 h after treatment with a MAMP, flg22 or inoculation with Pseudomonas syringae pv. tomato DC3000 ( Pst DC3000) hrcC mutant, which is deficient in TTSS function. Disruptions of SA signaling components, such as SID2 and PAD4 , strongly affected MAMP-triggered responses monitored by expression profiling. We found two groups of genes that were induced by Pst DC3000 hrcC in an SA-dependent manner. One group was SID2 -dependent at all time points, whereas the other was SID2 -independent at early time points and SID2 -dependent at later time points. Thus, the expression of the latter genes responds to MAMPs through both SA-independent and SA-dependent signaling mechanisms. Strong resistance to Pst DC3000 hrcC was dependent on SA signaling. These results indicate that the SA increase triggered by MAMPs is a major component of the MAMP-triggered signaling mechanism, explaining the overlapping spectra of MAMP-triggered and SA-mediated responses.