Shahzad Bhatti

ATM protein kinase: the linchpin of cellular defenses to stress

ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration. Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients.

PDGF: the nuts and bolts of signalling toolbox

PDGF is a growth factor and is extensively involved in multi-dimensional cellular dynamics. It switches on a plethora of molecules other than its classical pathway. It is engaged in various transitions of development; however, if the unleashed potentials lead astray, it brings forth tumourigenesis. Conventionally, it has been assumed that the components of this signalling pathway show fidelity and act with a high degree of autonomy. However, as illustrated by the PDGF signal transduction, reinterpretation of recent data suggests that machinery is often shared between multiple pathways, and other components crosstalk to each other through multiple mechanisms. It is important to note that metastatic cascade is an intricate process that we have only begun to understand in recent years. Many of the early steps of this PDGF cascade are not readily targetable in the clinic. In this review, we will unravel the paradoxes with reference to mitrons and cellular plasticity and discuss how disruption of signalling cascade triggers cellular proliferation phase transition and metastasis. We will also focus on the therapeutic interventions to counteract resultant molecular disorders.

NutriTRAILomics in prostate cancer: time to have two strings to one’s bow

The astonishing development of broad genomics and proteomics tools have catalyzed a new era in both therapeutic interventions and nutrition in prostate cancer. The terms pharmacogenomics and nutrigenomics have been derived out of their genetic forbears as large-scale genomics technologies have been established in the last decade. It is unquestionable that rationale of both disciplines is to individualize or personalize medicine and food and nutrition, and eventually health, by tailoring the drug or the food to the individual genotype. The purpose of this review is to significantly inspect results from current research concerning the mechanisms of action of phytonutrients and potential effects on prostate cancer. Substantial emerging data supports the synergistic adiministration of nutraceuticals with TRAIL in prostate cancer progression to circumvent TRAIL refractoriness. Nonetheless, developing novel scientific methods for discovery, validation, characterization and standardization of these multicomponent phyto-therapeutics is vital to their recognition into mainstream medicine. The key to interpret a personalized response is a greater comprehension of nutrigenomics, proteomics and metabolomics.

TRPM channels: same ballpark, different players, and different rules in immunogenetics

Transient receptor potential (TRP) channels belong to a large family of cation channels and are the “border guards” predominantly localized to the plasma membrane. Research over the years has considerably and highly developed the knowledge of expression and functional aspects of the TRPM channels. A closer look at the channel dynamics has dismantled undeniable substantiation for multifaceted roles for TRPM channel-mediated extracellular Ca(2+) influx in several physiological and pathophysiological functions. Given the wealth of literature unfolding the multiple roles of TRP channels in physiology in a very extensive range of different mammalian tissues, this review confines itself to the literature describing the multiple roles of TRPM channels in diabetes, smooth muscle cell regulation, immunological responses, and emerging aspects of cancer. We also focus on differential activities of TRPM channels after post-transcriptional and post-translational processing and their exquisite roles at various cellular and molecular levels.

Breast Cancer Proteome Takes More Than Two to Tango on TRAIL: Beat Them at Their Own Game

Breast carcinogenesis is a multidimensional disease that has resisted drug-related solutions to date because of heterogeneity, disorganized spatiotemporal behavior of signal transduction cascades, cell cycle checkpoints, cell transition, plasticity, and impaired pro-apoptotic response. These synchronized oncogenic events, including protein–protein interaction, transcriptional–regulatory, and signaling networks, trigger genomic and transcriptional disturbances in TRAIL-mediated signaling network neighborhoods. Therefore, tumor cells often acquire the ability to escape death by suppressing cell death pathways that normally function to eliminate damaged and harmful cells. This review describes the TRAIL-mediated cell death signaling pathways, the interactions between these pathways, and the ways in which these pathways are deregulated in breast cancer.

TRAIL and guardian angel of genome integrity: ATM boards TRAIL blazer

Prostate cancer is a multifaceted progressive multistep disorder that arises because of accumulation of genetic and epigenetic abnormalities, which escort to the transformation of normal cells into malignant derivatives. Despite tremendous strides have been made in the understanding of prostate cancer biology, yet approaches towards cancer-targeted therapy still face confrontations in standardization. This review brings to attention, the regulators in complex genetic backgrounds to enlighten our understanding of transformation and metastasis in human systems. Recent evidence gives a clue that prostate cancer may be linked to deregulated DNA damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints; apoptosis and DNA repair result in prostate cancer progression and aggressiveness. An insight of the orchestration between DNA damage-based molecular responses and TRAIL provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

While at Rome miRNA and TRAIL Do Whatever BCR-ABL Commands to Do

It is a well-acclaimed fact that proteins expressed as a consequence of oncogenic fusions, mutations or amplifications can facilitate ectopic protein–protein interactions that re-wire signal dissemination pathways, in a manner that escalates malignancy. BCR-ABL-mediated signal transduction cascades in leukemic cells are assembled and modulated by a finely controlled network of protein–protein interactions, mediated by characteristic signaling domains and their respective binding motifs. BCR-ABL functions in a cell context-specific and cell type-specific manner to integrate signals that affect uncontrolled cellular proliferation. In this review, we draw attention to the recent progress made in outlining resistance against TRAIL-mediated apoptosis and diametrically opposed roles of miRNAs in BCR-ABL-positive leukemic cells. BCR-ABL governs carcinogenesis through well-organized web of antiapoptotic proteins and over-expressed oncomirs which target death receptors and pro-apoptotic genes. Set of oncomirs which inversely correlate with expression of TRAIL via suppression of SMAD is an important dimension which is gradually gaining attention of the researchers. Contrary to this, some current findings show a new role of BCR-ABL in nucleus with spotlight on apoptosis. It seems obvious that genetic heterogeneity of leukemias poses therapeutic challenges, and pharmacological agents that target components of the cancer promoting nano-machinery still need broad experimental validation to be considered competent as a component of the therapeutic arsenal for this group of diseases. Rapidly developing technologies are empowering us to explain the molecular “nature” of a patient and/or tumor and with this integration of personalized medicine, with maximized efficacy, cost effectiveness will hopefully improve survival chances of the patient.

SMURF and NEDD4: Sharp Shooters Monitor the Gate Keepers and Ion Traffic Controllers of Lead Astray Cell

It is becoming increasingly apparent that a complex bar code underlies the quantitative aspects of extracellular signal regulation. Cell type-specific and context-dependent transcriptional programs are triggered by sophisticated nanomachinery consisting of HECT enzymes which monitor signal generation, transduction and termination. How the HECT enzymes safeguard spatiotemporal organization was a fundamental question towards understanding the process of protein degradation and its functions in diverse biological processes. In this review we will dismantle how HECT E3 enzymes regulate the trafficking of many receptors, channels and transporters as well as how HECT enzymes negatively regulate each other. There is accumulating evidence that suggests an undeniable role of HECT enzymes in regulating mediators of the Wnt signal-transduction cascade. By contrast, little is known about the crosstalk of HECT enzymes with ATM and TRAIL in prostate cancer, but several hints have emerged. This review provides a broader snapshot for studying multiple pathways in parallel, rather than as separate entities.

Prostate cancer is known by the companionship with ATM and miRNA it keeps: craftsmen of translation have dual behaviour with tailors of life thread

Research on prostate cancer progression has focused extensively on the concept of miRNA, which can operate either as promoters or as suppressors of carcinogenesis. Moreover, recent genetic studies and emerging functional work show that strikingly similar and overlapping pathways are involved in prostate carcinogenesis. Unswervingly, these elements constitute a recently explored ‘network of networks’ that dynamically reorganizes during DNA damage and is responsible for positively or negatively regulating genome organization and integrity. We consider these facets of convergence and discuss how insights from diametrically opposed interactions of ataxia–telangiectasia mutated and mitrons can inform us about, and possibly help us to get a step closer to personalized medicine. Copyright

One size fits all in prostate cancer: a story tale whose time has come and gone

The touchstone to evaluate accurately the aggressiveness and invasiveness of prostate cancer is something of a holy grail in the facet of urologic oncology. Gene expression and sequencing studies have improved our interpretations of the genetic determinants of the disease but are unsuccessful in the establishment of any unified classification to improve the molecular stratification. These questions addressing failure in rational drug design are difficult to answer in the multifaceted and heterogeneous pathogenesis of prostate cancer. In this review, we have developed a roadmap of the “recalcitrant prostate cancer proteome” to recognize the aspects of prostate cancer that may be helpful in effectively translating these findings to the clinic.