Tissue disorganisation is one of the main hallmarks of cancer. Polarity proteins are responsible for the arrangement of cells within epithelial tissues through the asymmetric organisation of cellular ...components. Partition defective 3 (PARD3) is a master regulator of the Par polarity complex primarily due to its ability to form large complexes via its self-homologous binding domain. In addition to its role in polarity, PARD3 is a scaffolding protein that binds to intracellular signalling molecules, many of which are frequently deregulated in cancer. The role of PARD3 has been implicated in multiple solid cancers as either a tumour suppressor or promoter. This dual functionality is both physiologically and cell context dependent. In this review, we will discuss PARD3's role in tumourigenesis in both laboratory and clinical settings. We will also review several of the mechanisms underpinning PARD3's function including its association with intracellular signalling pathways and its role in the regulation of asymmetric cell division.
There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common ...deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed.
Leucine-rich repeat kinase 2 (LRRK2) is genetically implicated in both familial and sporadic Parkinson's disease (PD). Moreover, LRRK2 has emerged as a compelling therapeutic target for the treatment ...of PD. Consequently, there is much interest in understanding LRRK2 and its role in PD pathogenesis. LRRK2 is constitutively phosphorylated on two serines, S910 and S935, that are required for interaction of LRRK2 with members of the 14-3-3 family of scaffolding proteins. Pathogenic LRRK2 missense mutations impair the phosphorylation of LRRK2 at these sites, but whether this contributes to PD pathology is unclear. To better understand how loss of LRRK2 phosphorylation relates to PD pathology, we have studied double knockin mice in which Lrrk2's serine 910 and 935 have both been mutated to alanine and can therefore no longer be phosphorylated. Nigrostriatal PD pathology was assessed in adult mice, aged mice, and mice inoculated with α-synuclein fibrils. Under all paradigms there was evidence of early PD pathology in the striatum of the knockin mice, namely alterations in dopamine regulating proteins and accumulation of α-synuclein. Striatal pathology was accompanied by a significant decrease in the number of astrocytes in the knockin mice. Despite striatal pathology, there was no degeneration of dopamine neurons in the substantia nigra and no evidence of a PD motor phenotype in the knockin mice. Our results suggest that modulation of LRRK2 serine 910 and 935 phosphorylation sites may have implications for dopamine turnover and astrocyte function, but loss of phosphorylation at these residues is not sufficient to induce PD neurodegeneration.
•LRRK2 S910 and S935 phosphorylation deficient mice have a propensity to accumulate α-synuclein.•LRRK2 S910 and S935 phosphorylation deficient mice have mild PD pathology with reduced astrocytes.•Complete loss of LRRK2 S910 and S935 phosphorylation was insufficient to induce neurodegeneration.
Nucleophosmin gene mutations are frequently reported in acute myeloid leukemia (AML) patients with normal karyotype, which is also frequently associated with internal tandem duplication mutations in ...the FMS-like tyrosine kinase-3 gene. We sought to detect the nucleophosmin and FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutations among Iranian patients with AML and to assess the relationship between these mutations and the subtypes of the disease.
Cross-sectional study of patients referred during 2007 through 2009.
Bone marrow and peripheral blood samples of 131 AML patients were randomly collected at the time of diagnosis and prior to treatment and the DNA extracted. After amplifying the nucleophosmin and FLT3 gene regions, positive cases were screened by conformation-sensitive gel electrophoresis and agarose gel electrophoresis techniques.
Of 131 patients, 23 (17.5%) (0.95% CI=0.107-0.244) had nucleophosmin gene mutations. The highest frequency of such mutations was found among the subtypes of M4 (30.4%), M3 (21.7%) and M5 (17.4%). There was a high frequency of these mutations in the M3 subtype as well as a high frequency of allele D in all subtypes. Also, 21 (16.0%) samples (0.95% CI=0.092-0.229) had FLT3/ITD mutation, of which 8 samples had mutant nucleophosmin (8 of 23, 35%), and another 13 samples had wild-type nucleophosmin gene (13 of 108, 12%). There was a high degree of association between the occurrence of nucleophosmin and FLT3/ITD mutations (P=.012).
Our data showed a high frequency of NPM1 mutations in the monocytic subtypes of AML, as well as a high degree of association between the occurrence of NPM1 and FLT3/ITD mutations.
Major advances in understanding how genetics underlies Parkinson's disease (PD) have provided new opportunities for understanding disease pathogenesis and potential new targets for therapeutic ...intervention. One such target is leucine-rich repeat kinase 2 (LRRK2), an enigmatic enzyme implicated in both familial and idiopathic PD risk. Both academia and industry have promoted the development of potent and selective inhibitors of LRRK2, and these are currently being employed to assess the safety and efficacy of such compounds in preclinical models of PD. This review examines the evidence that LRRK2 kinase activity contributes to the pathogenesis of PD and outlines recent progress on inhibitor development and early results from preclinical safety and efficacy testing. This review also looks at some of the challenges remaining for translation of LRRK2 inhibitors to the clinic, if indeed this is ultimately warranted. As a disease with no current cure that is increasing in prevalence in line with an aging population, there is much need for developing new treatments for PD, and targeting LRRK2 is currently a promising option.
Missense mutations in glucocerebrosidase (GBA1) that impair the activity of the encoded lysosomal lipid metabolism enzyme (GCase) are linked to an increased risk of Parkinson's disease. However, ...reduced GCase activity is also found in brain tissue from Parkinson's disease patients without GBA1 mutations, implicating GCase dysfunction in the more common idiopathic form of Parkinson's disease. GCase is very highly expressed in monocytes, and thus we measured GCase activity in blood samples from recently diagnosed Parkinson's disease patients. Flow cytometry and immunoblotting assays were used to measure levels of GCase activity and protein in monocytes and lymphocytes from patients with Parkinson's disease (n = 48) and matched controls (n = 44). Gene sequencing was performed to screen participants for GBA1 missense mutations. In the Parkinson's disease patients, GCase activity was significantly reduced in monocytes, but not lymphocytes, compared to controls, even when GBA1 mutation carriers were excluded. Monocyte GCase activity correlated with plasma ceramide levels in the Parkinson's disease patients. Our results add to evidence for GCase dysfunction in idiopathic Parkinson's disease and warrant further work to determine if monocyte GCase activity associates with Parkinson's disease progression.
Cell polarity is a critical feature of multiple aspects of cell biology e.g. cell division and differentiation. Disrupted polarity network is well established in epithelial cancers where the polarity ...regulators act as tumour-suppressors or oncogenes. In the haematopoietic system, polarity proteins regulate asymmetric cell division (ACD) of haematopoietic stem cells (HSCs). ACD is central to the maintenance of normal haematopoiesis, ensuring the retention of self-renewal and differentiation potentials of HSCs. Disrupted ACD is associated with leukaemia transformation as leukemic cells lose the ability to differentiate and instead gain the ability to self-renew. Considering this and the role of polarity proteins in ACD, understanding how they regulate HSCs ACD or contribute to leukaemia is of major importance. We examined the role of polarity protein PAR3 in acute myeloid leukaemia (AML). To determine the role of PAR3 loss in haematopoiesis, we utilised a Par3 conditional knockout mouse model. For the human model, Par3 was knocked out in AML cell lines using CRISPR/Cas9. We found that PAR3 is differentially expressed in haematopoietic progenitors and their more differentiated progeny. PAR3 loss in a pre-clinical model of murine AML led to a significant increase in the proportion and number of granulocyte/macrophage progenitors, which are the hyperproliferative cancer stem cells. This was associated with deregulation of MAPK and HIPPO signalling pathways in PAR3 KO animals. To study the cellular and molecular mechanisms of PAR3 in human AML, we have successfully knocked out the Par3 in several human AML cell lines. The role of PAR3 in ACD is being studied by examining the cell cycle status using live cell imaging, cell differentiation, polarised inheritance of cell fate determinants, and mitotic spindle positioning. In conclusion, PAR3 acts as a tumour suppressor in AML.
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