IRBIT a Master Regulator of Cell Physiology

(excerpt) Hormones and neurotransmitters regulate cell functions by binding to their receptors, which activate intracellular signaling and produce the physiological response [1]. There are several intracellular pathways, including but not limited to, leading to the activation of protein kinases, phosphatases and increase in intracellular calcium (Ca2+) [1]

When the time is ripe.

The diverse effects of the plant hormone ethylene on development and growth are shaped by the actions of a master regulator of transcription, EIN3

PTEN: A master regulator of neuronal structure, function, and plasticity.

PTEN (phosphatase and tensin homolog on chromosome ten) is a dual protein/lipid phosphatase that dephosphorylates PIP3, thereby inhibiting the AKT/mTOR pathway. This inhibition ultimately decreases protein translation, cell proliferation and cell growth. In the central nervous system, inhibition of PTEN leads to increased stem cell proliferation, somatic, dendritic and axonal growth, accelerated spine maturation, diminished synaptic plasticity, and altered intrinsic excitability. In agreement with these findings, patients carrying single-copy inactivating mutations of PTEN suffer from autism, macrocephaly, mental retardation, and epilepsy.(1) (-) (9) Understanding the mechanisms through which PTEN modulates the structure, function, and plasticity of cortical networks is a major focus of study. Preventing and reversing the changes induced by loss of Pten in model animals will pave the way for treatments in humans

mTOR: The Master Regulator

The mammalian target of rapamycin (mTOR) kinase integrates cues from nutrients and growth factors, acting as a nexus point for cellular signals to control growth, metabolism, and longevity. Deregulation of either of mTOR's two complexes, mTORC1 or mTORC2, leads to diseases of metabolism, including cancer and diabetes. In this issue's Select, insights into the extent of mTOR's oncogenic capabilities come to light, and it appears that an old drug (rapamycin) has some new tricks in vivo

Interleukin-12: A master regulator

Early resistance to pathogens requires a swift response from NK cells. In 1989, Giorgio Trinchieri identified an NK growth factor and activator, later called interleukin-12 (IL-12). This discovery helped reveal the regulatory link between innate and adaptive immunity

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype.

Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC

IRBIT a Master Regulator of Cell Physiology

(excerpt) Hormones and neurotransmitters regulate cell functions by binding to their receptors, which activate intracellular signaling and produce the physiological response [1]. There are several intracellular pathways, including but not limited to, leading to the activation of protein kinases, phosphatases and increase in intracellular calcium (Ca2+) [1]

Rab7a: the master regulator of vesicular trafficking

The membrane flow of eukaryotic cells occurs through vesicles that bud from a donor compartment, move and fuse with an acceptor compartment. Rab (Ras-related in brain), which belong to the Ras superfamily of small GTPases, emerged as a central player of vesicle mobility in both secretory and endocytic pathway, Rab7a being a master regulator of late endocytic trafficking. Elucidation of how mutant or dysregulated Rab7 GTPase and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab7 or associated regulatory proteins causes numerous human genetic diseases. Cancer and neurodegeneration represent examples of acquired human diseases resulting from the up- or down-regulation or aberrant function of Rab7. The broad range of physiologic processes affected by altered Rab7 activity is based on its pivotal roles in membrane trafficking and signaling. The Rab7-regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate docking and fusion with the target membranes control cell metabolism, growth and differentiation. In this review, role of Rab7 in endocytosis is evaluated to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab7 activity alter endocytic trafficking that underlie neurologic, lipid storage, and bone disorders as well as cancer.Biomedical Reviews 2014; 25: 67-81

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

A combination of transcriptional and microRNA regulation improves the stability of the relative concentrations of target genes

It is well known that, under suitable conditions, microRNAs are able to fine tune the relative concentration of their targets to any desired value. We show that this function is particularly effective when one of the targets is a Transcription Factor (TF) which regulates the other targets. This combination defines a new class of feed-forward loops (FFLs) in which the microRNA plays the role of master regulator. Using both deterministic and stochastic equations we show that these FFLs are indeed able not only to fine-tune the TF/target ratio to any desired value as a function of the miRNA concentration but also, thanks to the peculiar topology of the circuit, to ensures the stability of this ratio against stochastic fluctuations. These two effects are due to the interplay between the direct transcriptional regulation and the indirect TF/Target interaction due to competition of TF and target for miRNA binding (the so called "sponge effect"). We then perform a genome wide search of these FFLs in the human regulatory network and show that they are characterizedby a very peculiar enrichment pattern. In particular they are strongly enriched in all the situations in which the TF and its target have to be precisely kept at the same concentration notwithstanding the environmental noise. As an example we discuss the FFL involving E2F1 as Transcription Factor, RB1 as target and miR-17 family as master regulator. These FFLs ensure a tight control of the E2F/RB ratio which in turns ensures the stability of the transition from the G0/G1 to the S phase in quiescent cells.Comment: 23 pages, 10 figure