St Edmunds College

Shillong, India

St Edmunds College

Shillong, India

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Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2015

Metabolic homeostasis during long-term adaptation in animals is primarily achieved by controlling the expression of metabolic genes by a plethora of cellular transcription factors. The nuclear receptor (NR) superfamily in eukaryotes is an assembly of diverse receptors working as transcriptional regulators of multiple genes. The orphan estrogen-related receptor alpha (ERRα) is one such receptor of the NR superfamily with significant influence on numerous metabolic and other genes. Although it is presently unknown as to which endogenous hormones or ligands activate ERRα, nevertheless it regulates a host of genes whose products participate in various metabolic pathways. Studies over the years show new and interesting data that add to the growing knowledge on ERRα and metabolic regulation. For instance, novel findings indicate existence of mTOR/ERRα regulatory axis and also that ERRα control PGC-1α expression which potentially have significant impact on cellular metabolism. Data show that ERRα exerts its metabolic control by regulating the expression of SIRT5 that influences oxygen consumption and ATP generation. Moreover, ERRα has a role in creatine and lactate uptake in skeletal muscle which is important towards energy generation and contraction. This review is focused on the new insights gained into ERRα regulation of metabolism, networks and pathways that have important consequences in maintaining metabolic homeostasis including development of cancer. © 2015 Informa Healthcare USA, Inc.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2013

The orphan nuclear receptors (ONRs) are a vital class of transcriptional regulators belonging to the larger nuclear receptors (NRs) superfamily in higher eukaryotes. As a result of non-identification of endogenous physiological ligands for this class of NRs, they are designated as "orphans". The ONRs on receiving appropriate signals translate into specific gene regulation. Elaborate studies on the ONRs in the past two decades have revealed crucial biological functions controlled by them relating to general metabolism, immunity, organogenesis, angiogenesis, growth and development, and numerous other tissue physiologies. Over the years, many of the ONRs have been studied for their participatory role in human health and disease. Results obtained are encouraging and interesting and shows a number of ONRs does modulate several patho-physiological conditions such as cancer and diabetes. This review discusses the current status about the interplay between select ONRs in cancer and diabetes. © 2013 Informa Healthcare USA, Inc.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2012

Coordinated and tight regulation of gene expression in metazoans is essential for cellular homeostasis and functions. Tissue-and cell-specific regulatory factors are indispensable and a wide variety of them exist to regulate genes. A family of transcriptional factors was identified in the past two decades through gene cloning studies and was informally referred as "orphan receptors", as appropriate endogenous ligands for such receptors were unknown. One of the subclasses of such receptors is known as the estrogen-related receptors (ERRs), which include three isoforms, namely ERRα, ERRβ and ERRγ. Over the past one decade, unprecedented knowledge about the ERRs biology has been generated, indicating their vital roles in various metabolic and physiological activities in animals. The ERRs cellular action is largely attributed to its interaction with a wide variety of other nuclear receptors, including some orphan nuclear receptors, and thereby can modulate diverse array of genes involved in metabolism and animal physiology. Studies using genome-wide location analyses, microarray and functional genomics, including ERR-specific null mice have revealed a number of pathways controlled by the ERRs. In this context, new and recent information on the biological functions of ERRs are being reviewed. © 2012 Informa Healthcare USA, Inc.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2015

Cancer is perhaps the fastest growing non-communicable disease in the human population worldwide. Although the molecular mechanism of cancer initiation and progression is known to some extent, however, the majority of pathways responsible for its onset, development and progression are largely unknown. Many members of the nuclear receptors (NRs) superfamily of transcriptional factors have key roles in cancer. Estrogen-related receptor alpha (ERRα) is one of the members of the NR superfamily and studies have linked it with a wide variety of cancers. In endocrine-related cancers such as breast cancer, ERRα regulates a number of target genes directing cell proliferation and growth independent of estrogen receptor alpha (ERα). Knockdown of ERRα in a number of cancer tissues and cell lines significantly reduced tumor growth and malignancy indicating dependence on ERRα activity. The pro-angiogenesis factor vascular endothelial growth factor expression has been shown to be regulated by ERRα and has implications in several types of cancer. The effect of ERRα on cancers seems to be multipronged via regulation of cell cycle regulators, osteopontin, hypoxia inducible factor-1 as well as several energy metabolism genes that are part of glycolysis, TCA cycle, lipogenesis, etc., providing a metabolic twist to cancer. In this article, the action of ERRα on various types of cancers including new developments in this field shall be reviewed. © 2015 Taylor & Francis.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2011

In classical endocrinology, receptors are molecules that bind a hormone or a ligand to transduce signal within a target cell. Later, however, many intracellular receptors have been discovered in mammals, which have not been shown to bind endogenous ligands and are now are referred as "orphan receptors." The orphan receptors share high degree of structural and functional homology with the classical nuclear receptors (NRs) and are now part of the NR superfamily and therefore referred as orphan nuclear receptors (ONRs). Interestingly, however, ONR members are not evolutionarily or functionally linked and they form a highly diverse group within the NR superfamily. In mammals, ONRs exhibit great functional diversity and majority of them are expressed in a tissue-specific fashion. In the past one decade, functional studies have revealed that they are mediators of multitude of crucial metabolic, developmental, reproductive, and immunological functions in mammals. Emerging studies also indicate the role of ONRs in the onset of several complex human diseases and hence they may be potential candidates for therapeutic drug targeting in the future. © 2011 Informa Healthcare USA, Inc.


Ranhotra H.S.,St Edmunds College
Indian Journal of Biochemistry and Biophysics | Year: 2010

The peroxisome proliferator-activated receptor (PPAR) gamma co-activator 1 alpha (PGC-1α), a signal-sensing transcriptional co-activator in association with many nuclear receptors regulates various genes that control energy balance in animals. In this study, the effect of long-term caloric restriction (CR) (alternate days of fasting for 3 months) on the expression of PGC-1α protein in various tissues was investigated in mice. Western blot analyses showed positive immunoreactive PGC-1α (~92 kDa) signal from various tissues. Heart, kidney and skeletal muscles expressed significant levels of PGC-1α, while a comparatively lower level was detected in the liver, small intestine and brain. The expression of PGC-1α was the highest and lowest in the heart and liver respectively. CR mice exhibited a significant increase in PGC-1a level in the heart (5.13-fold), kidney (3.57-fold), skeletal muscle (3.02-fold), liver (2.60-fold), small intestine (2.45-fold) and brain (2.05-fold), compared to normal (ad libitum) fed. The elevation in PGC-1α level, especially in highly oxidative tissues such as heart, kidney and skeletal muscle of CR mice might synergistically up-regulate genes that require PGC-1α co-activation. Taken together, the up-regulation of PGC-1α expression might potentially support optimal energy metabolism and biochemical adaptation, necessary for maintaining energy homeostasis during long-term CR.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2012

The retinoic acid receptor-related orphan receptors (RORs) are an important subfamily of transcriptional regulators of the nuclear receptors superfamily. Their discovery over a decade ago by gene cloning strategy have revealed three major isoforms of these orphan receptors in animals. Generation and analyses of isoform-specific ROR null mice have provided revealed-vital roles for the RORs in animals. The RORs undoubtedly participate in a host of biological functions such a metabolism, immunity, development and differentiation, angiogenesis, circadian clock, xenobiotic/drug metabolism and other tissue physiologies for optimal animal survival. Moreover, intense work in the last one decade also revealed a host of human diseases being modulated by the RORs. A number of diseases, such as cancer, autoimmune diseases, inflammation, osteoporosis, metabolic syndrome etc., strongly support the involvement of RORs in their onset and progression. By involving in such diseases, the RORs are indeed a critical factor for optimal cell function and are being intensely investigated as novel targets for drug interventions in the treatment of various diseases. This review focuses on the current knowledge and status about RORs in a number of human disease conditions. © 2012 Informa Healthcare USA, Inc.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2010

The estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor (ONR) that by binding to DNA sites controls gene expression in association with coactivators and corepressors. ERRα was the first ONR to be identified; however, its natural endogenous ligand(s) is still unknown. ERRα by acting as a transcription factor has been shown to regulate a large array of genes, thereby controlling numerous metabolic pathways and other biological functions in animals. Of late, the expression of ERRα has been detected in several tissues, including those with high metabolic activities and energy demand. Presently, the control of energy balance by ERRα seems to be its prime role. The nonavailability of endogenous ligand for ERRα has not impeded the study of its functions. In fact, most of the present knowledge of the biological roles of ERRα has evolved from in-depth biochemical, overexpression, genomic, including functional genomics studies, and also through the generation of intact ERRα knockout (null) mice. Interestingly, over the past few years, growing evidence suggests interplay between ERRα and various human metabolic diseases such as diabetes, obesity, and heart disease. Also, there are strong indications of the involvement of ERRα in cancer initiation and progression. Interestingly, this makes ERRα a suitable, direct target for pharmacological intervention in treating such diseases. This review focuses on the overall developments and recent advances in understanding the role of ERRα in metabolism and other biological functions, including its role in human diseases. © 2010 Informa UK Ltd.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2015

The NR4A subfamily is orphan nuclear receptors that belong to the larger nuclear receptors (NRs) superfamily of eukaryotic transcription factors. The NR4A subfamily includes three members, namely Nur77 (NR4A1), Nurr1 (NR4A2) and Nor1 (NR4A3) which are gene regulators and participate in diverse biological functions. Though the ligands for these receptors are presently unidentified, they are thought to be constitutively active. NR4A acts as molecular switches in gene regulation and their action is increasingly seen to be modulated by complex network of cellular signaling pathways. Members of the NR4A are expressed in tissue-specific fashion which indicates their selective control of various biological processes. Data reveal a host of functions governed by the NR4A subfamily members including general metabolism, immunity, cellular stress, memory, insulin sensitivity and cardiac homeostasis by regulating specific target genes whose products participates in such processes. Moreover, these receptors have a role in the onset and progression of various diseases such as various types of cancer, inflammation, atherosclerosis and obesity. In this review, a concise overview of the current understanding of the important metabolic roles governed by NR4A members including their participation in a number of diseases shall be provided. © 2014 Informa Healthcare USA, Inc.


Ranhotra H.S.,St Edmunds College
Journal of Receptors and Signal Transduction | Year: 2015

The estrogen-related receptor alpha (ERRα) governs multitude of biological functions by working as specific transcriptional regulator in animals. Over the past few years, one aspect of ERRα that has seen optimal progress is its control over the mitochondrial physiology. The ERRα not only regulates an array of nuclear genes devoted to mitochondrial functions but also numerous mitochondrial DNA genes that ultimately culminates into this organelles homeostasis. In fact, ERRα expression is correlated with genes whose functional products are part of the mitochondrial physiology. Studies have indicated that nearly half of the proteins encoded by the mitochondrial genome are regulated by ERRα. Moreover, ERRα controls vital mitochondrial processes such as oxidative metabolism through a network of protein kinases and by regulating the expression of sirtuins like Sirt3. Furthermore, new findings also show that ERRα regulate mitochondrial biogenesis in association with PGC family co-activators such as PGC-1-related co-activator and PGC-1β and also via cross-talk with mitogen-activated protein kinase kinases and PI3K/(AKT) signaling. The current understanding of the pathways and networks shows strong influence of ERRα in coordinating mitochondrial physiology. This review focuses on the new advances made in understanding the complex and important interface between ERRα and mitochondrial physiology. © 2014 Informa Healthcare USA, Inc.

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