IAPs as E3 ligases of Rac1 : shaping the move

Inhibitors of Apoptosis Proteins (IAPs) are well-studied E3 ubiquitin ligases predominantly known for regulation of apoptosis. We uncovered that IAPs can function as a direct E3 ubiquitin ligase of RhoGTPase Rac1. cIAP1 and XIAP directly conjugate polyubiquitin chains to Lysine 147 of activated Rac1 and target it for proteasomal degradation. Consistently, loss of these IAPs by various strategies led to stabilization of Rac1 and mesenchymal mode of migration in tumor cells. IAPs also regulate Rac1 degradation upon RhoGDI1 depletion and CNF1 toxin treatment. Our observations revealed an evolutionarily conserved role of IAPs in regulating Rac1 stability shedding light on to the mechanisms behind ubiquitination–dependent inactivation of Rac1 signaling

Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications

Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions

Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications

Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions

IAPs on the move : role of inhibitors of apoptosis proteins in cell migration

Inhibitors of Apoptosis Proteins (IAPs) are a class of highly conserved proteins predominantly known for the regulation of caspases and immune signaling. However, recent evidence suggests a crucial role for these molecules in the regulation of tumor cell shape and migration by controlling MAPK, NF-κB and Rho GTPases. IAPs directly control Rho GTPases, thus regulating cell shape and migration. For instance, XIAP and cIAP1 function as the direct E3 ubiquitin ligases of Rac1 and target it for proteasomal degradation. IAPs are differentially expressed in tumor cells and have been targeted by several cancer therapeutic drugs that are currently in clinical trials. Here, we summarize the current knowledge on the role of IAPs in the regulation of cell migration and discuss the possible implications of these observations in regulating tumor cell metastases

Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells

As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-κB (NF-κB) signaling and a tumor necrosis factor-α (TNFα)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth in vivo underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-κB DNA binding and enhanced NF-κB transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-κB DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-κB pathway. BV6-stimulated NF-κB activation leads to elevated mRNA levels of TNFα and additional NF-κB target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-κB signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-κB target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNFα autocrine/paracrine loop by the TNFα-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-κB signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics

Master of Science

thesisIn today's fast growing world of health care, the volume of drug information needed to provide competent care to patients is overwhelming. On average, health care professionals have two informational needs for every three patients seen which are either related to diagnosis or treatment. Therefore, seeking appropriate drug information to answer these informational needs is an important and valuable element of health care. Drug information can be obtained from different sources. Traditional sources like books, journals, meeting with colleagues, physicians' desk reference (PDR) or modern sources like the Internet (Google, Wikipedia), medical databases and medical literature indices. The information so obtained from these sources helps health care professionals to fill the gap in knowledge on new drugs and improve patient care. Therefore, the purpose of this study is (1) to identify health care professionals (HCPs) reported frequencies of use for different drug information sources in the University of Utah Community Clinics to obtain drug information (2) to descriptively find out of if there existed a difference between clinicians and pharmacists in their drug information seeking behaviors. The study design was cross-sectional and utilized a survey questionnaire to capture the drug information-seeking behaviors among health care professionals The Mission Based Survey Management tool was used to send out the surveys. iv The survey response rate was 55%. Clinicians most frequently reported to use drug information databases (46%) followed by personal digital assistants (PDAs) (23%) and electronic sources (18%) while pharmacists most frequently reported to use drug information databases (78%) followed by electronic sources (28%) and medical literature indices (19%). Clinicians were more likely to use PDAs to access drug information than pharmacists which could be due to portability and easier access to drug information via PDAs at point of care. Based on the results obtained from the study, it is reasonable to conclude that when clinicians and pharmacists were given a wide range of sources to choose from to seek drug information, most clinicians and pharmacist preferred to use drug information databases to obtain new drug information as compared to the traditional sources like books, journals and colleagues. Modern and improved technological sources of drug information have taken the place of traditional sources of drug information, reducing health care professionals' trips to the library or to the printed medical journals and books, eventually improving patient care

Dominance of Self-hood in Shagun, the Mother: A Study of Manju Kapur’s Custody

Marriage as an arranged one is a religious ceremony. A man and a woman who enter into marital life as husband and wife promise that they will live together till the end of their earthly life braving all the seasons of life. Besides, as husband and wife, they are destined to enter into conjugal relationship for procreation as well as continuation of their posterity on earth. The wife begets children from what her husband gives during their sexual relationship and thus both become blessed parents. The wife as a mother lives only for her children and husband. She never entertains any thought other than dedicating herself to the welfare of her family. The husband as a father provides life, comforts and security to his family. But in the modern days, such established conventions have gone into oblivion because of the absence of understanding and genuine love, the lack of conjugal bliss and the dominance of ego and selfishness between the married ones. Both are tempted to go astray in their ways of life affecting the peace and happiness at home. Men hardly divorce their wives but women do on various unimaginable reasons known only to them. The woman who is selfish to the core never worries about leaving children to their fate just because they are born to him. She either remarries or lives in relationship with another even without marriage to satisfy her selfishness. Her womanliness occupies the entire space of her heart dethroning the spirit of motherhood. Whatever happens to her, she should stay back at her marital home as the mother of her children without any conjugal relationship with her husband but she does not do so because her selfishness to quench her personal interest for sex reigns supreme.  This is what Manju Kapur has portrayed through the mother character Shagun in her novel Custody