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Two major types of leukemogenic BCR-ABL fusion proteins are p190BCR-ABLand p210BCR-ABL. Although the two fusion proteins are closely related, they can lead to different clinical outcomes. A thorough understanding of the signaling programs employed by these two fusion proteins is necessary to explain these clinical differences. We took an integrated approach by coupling protein–protein interaction analysis using biotinylation identification with global phosphorylation analysis to investigate the differences in signaling between these two fusion proteins. Our findings suggest that p190BCR-ABL and p210BCR-ABL differentially activate important signaling pathways, such as JAK-STAT, and engage with molecules that indicate interaction with different subcellular compartments. In the case of p210BCR-ABL, we observed an increased engagement of molecules active proximal to the membrane and in the case of p190BCR-ABL, an engagement of molecules of the cytoskeleton. These differences in signaling could underlie the distinct leukemogenic process induced by these two protein variants.Leukemia advance online publication, 28 March 2017; doi:10.1038/leu.2017.61. © 2017 Macmillan Publishers Limited, part of Springer Nature.


Barker N.,Singapore Institute of Medical Biology | Barker N.,University of Edinburgh | Barker N.,National University of Singapore
Nature Reviews Molecular Cell Biology | Year: 2014

Small populations of adult stem cells are responsible for the remarkable ability of the epithelial lining of the intestine to be efficiently renewed and repaired throughout life. The recent discovery of specific markers for these stem cells, together with the development of new technologies to track endogenous stem cell activity in vivo and to exploit their ability to generate new epithelia ex vivo, has greatly improved our understanding of stem cell-driven homeostasis, regeneration and cancer in the intestine. These exciting new insights into the biology of intestinal stem cells have the potential to accelerate the development of stem cell-based therapies and ameliorate cancer treatments. © 2014 Macmillan Publishers Limited. All rights reserved.


Leushacke M.,Singapore Institute of Medical Biology | Barker N.,Singapore Institute of Medical Biology
Oncogene | Year: 2012

The extended longevity of many mammals imposes the need for an effective tissue renewal capacity within the vital organs to maintain optimal function. Resident adult stem cells are instrumental in delivering this renewal capacity by virtue of their characteristic ability to maintain themselves long-term as a population (self-renewal), whilst also supplying all functional cell-lineages of the respective tissue (multipotency). The homeostatic activity of these adult stem cell reservoirs is tailored to meet the specific renewal requirements of individual tissues through a combination of intrinsic genetic programming and local cues delivered from the surrounding environment (the niche). Considerable phenotypic diversity therefore exists between adult stem cell populations in different organs, making it a considerable challenge to identify broadly applicable markers that facilitate their identification and characterization. However, the 7-transmembrane receptor, Lgr5 has recently gained prominence as a marker of Wnt-regulated adult stem cell populations in the hair-follicle, intestine and stomach. A closely-related protein, Lgr6 marks adult stem cells responsible for fueling the renewal of the sebaceous gland and skin. The discovery of these markers has already greatly improved our understanding of stem cell biology in these rapidly renewing tissues and has major implications for the identification and isolation of human adult stem cell populations for exploitation of their regenerative medicine potential in the clinic. © 2012 Macmillan Publishers Limited All rights reserved.


Burke B.,Singapore Institute of Medical Biology | Stewart C.L.,Singapore Institute of Medical Biology
Current Topics in Developmental Biology | Year: 2014

In eukaryotes, the function of the cell's nucleus has primarily been considered to be the repository for the organism's genome. However, this rather simplistic view is undergoing a major shift, as it is increasingly apparent that the nucleus has functions extending beyond being a mere genome container. Recent findings have revealed that the structural composition of the nucleus changes during development and that many of these components exhibit cell- and tissue-specific differences. Increasing evidence is pointing to the nucleus being integral to the function of the interphase cytoskeleton, with changes to nuclear structural proteins having ramifications affecting cytoskeletal organization and the cell's interactions with the extracellular environment. Many of these functions originate at the nuclear periphery, comprising the nuclear envelope (NE) and underlying lamina. Together, they may act as a "hub" in integrating cellular functions including chromatin organization, transcriptional regulation, mechanosignaling, cytoskeletal organization, and signaling pathways. Interest in such an integral role has been largely stimulated by the discovery that many diseases and anomalies are caused by defects in proteins of the NE/lamina, the nuclear envelopathies, many of which, though rare, are providing insights into their more common variants that are some of the major issues of the twenty-first century public health. Here, we review the contributions that mouse mutants have made to our current understanding of the NE/lamina, their respective roles in disease and the use of mice in developing potential therapies for treating the diseases. © 2014 Elsevier Inc.


Burke B.,Singapore Institute of Medical Biology
Cell | Year: 2012

LINC complexes are structures embedded within the nuclear envelope that mechanically couple the nucleus and cytoskeleton. They consist of SUN domain proteins of the inner nuclear membrane associated with KASH domain proteins in the outer nuclear membrane. Atomic resolution structures of SUN-KASH pairs now provide new insight in to the mechanisms of LINC complex assembly. © 2012 Elsevier Inc.


Lo K.A.,Singapore Institute of Medical Biology
Bioscience reports | Year: 2013

Adipose tissue has a central role in the regulation of energy balance and homoeostasis. There are two main types of adipose tissue: WAT (white adipose tissue) and BAT (brown adipose tissue). WAT from certain depots, in response to appropriate stimuli, can undergo a process known as browning where it takes on characteristics of BAT, notably the induction of UCP1 (uncoupling protein 1) expression and the presence of multilocular lipid droplets and multiple mitochondria. How browning is regulated is an intense topic of investigation as it has the potential to tilt the energy balance from storage to expenditure, a strategy that holds promise to combat the growing epidemic of obesity and metabolic syndrome. This review focuses on the transcriptional regulators as well as various proteins and secreted mediators that have been shown to play a role in browning. Emphasis is on describing how many of these factors exert their effects by regulating the three main transcriptional regulators of classical BAT development, namely PRDM16 (PR domain containing 16), PPARγ (peroxisome proliferator-activated receptor γ) and PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which have been shown to be the key nodes in the regulation of inducible brown fat.


Horn H.F.,Singapore Institute of Medical Biology
Current Topics in Developmental Biology | Year: 2014

The LINC complex spans the nuclear envelope and plays critical roles in coordinating nuclear and cytoplasmic activities and in organizing nuclear and cytoskeletal features. LINC complexes are assembled from KASH and SUN-domain proteins, which interact in the nuclear envelope and form a physical link between the cytoskeleton and the nuclear interior. A number of diseases have been associated with mutations in genes coding for LINC complex proteins. Mouse models of LINC complex protein have provided valuable insight into LINC complex functions and into how these proteins contribute to the various diseases with which they have been associated. © 2014 Elsevier Inc.


Burke B.,Singapore Institute of Medical Biology | Stewart C.L.,Singapore Institute of Medical Biology
Nature Reviews Molecular Cell Biology | Year: 2013

The nuclear lamina is an important structural determinant for the nuclear envelope as a whole, attaching chromatin domains to the nuclear periphery and localizing some nuclear envelope proteins. The major components of the lamina are the A-type and B-type lamins, which are members of the intermediate filament protein family. Whereas the expression of A-type lamins is developmentally regulated, B-type lamins, as a class, are found in all cells. The association of B-type lamins with many aspects of nuclear function has led to the view that these are essential proteins, and there is growing evidence suggesting that they regulate cellular senescence. However, B-type lamins are dispensable in certain cell types in vivo, and neither A-type nor B-type lamins may be required in early embryos or embryonic stem cells. The picture that is beginning to emerge is of a complex network of interactions at the nuclear periphery that may be defined by cell-and tissue-specific functions. © 2012 Macmillan Publishers Limited. All rights reserved.


Messerschmidt D.M.,Singapore Institute of Medical Biology
Epigenetics | Year: 2012

Recent findings shed light on the coordination of two fundamen- tal, yet mechanistically opposing, pro- cesses in the early mammalian embryo. During the oocyte-to-embryo transi- tion and early preimplantation develop- ment nuclear reprogramming occurs. This resetting of the epigenome in maternal and paternal pronuclei to a ground state is the essential step ensur- ing totipotency in the zygote, the first embryonic stage. Radical, global DNA demethylation, which occurs actively in the paternal and passively in the maternal genome, is a prominent fea- ture of nuclear reprogramming; yet, this process poses a danger to a subset of methylated sequences that must be preserved for their germline to soma inheritance. Genomic imprinting and its importance were demonstrated three decades ago by a series of experiments generating non-viable mammalian uni-parental embryos. Indeed, imprinted loci, gene clusters with parent-of-origin specific gene expression patterns, must retain their differential methylation status acquired during gametogen-esis throughout embryogenesis and in adult tissues. It is just recently that the molecular players that protect/maintain imprinting marks during reprogram-ming in preimplantation embryos have been identified, in particular, an epigen-etic modifier complex formed by ZFP57 and TRIM28/KAP1. The interaction of these and other molecules with the newly formed embryonic chromatin and imprinted genes is discussed and high-lighted herein. © 2012 Landes Bioscience.


Messerschmidt D.M.,Agency for Science, Technology and Research Singapore | Knowles B.B.,The Jackson Laboratory | Knowles B.B.,Singapore Institute of Medical Biology | Solter D.,Singapore Institute of Medical Biology
Genes and Development | Year: 2014

Methylation of DNA is an essential epigenetic control mechanism in mammals. During embryonic development, cells are directed toward their future lineages, and DNA methylation poses a fundamental epigenetic barrier that guides and restricts differentiation and prevents regression into an undifferentiated state. DNA methylation also plays an important role in sex chromosome dosage compensation, the repression of retrotransposons that threaten genome integrity, the maintenance of genome stability, and the coordinated expression of imprinted genes. However, DNA methylation marks must be globally removed to allow for sexual reproduction and the adoption of the specialized, hypomethylated epigenome of the primordial germ cell and the preimplantation embryo. Recent technological advances in genome-wide DNA methylation analysis and the functional description of novel enzymatic DNA demethylation pathways have provided significant insights into the molecular processes that prepare the mammalian embryo for normal development. © 2014 Messerschmidt et al.

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