Autophagy in Model Organisms: Insights into Cancer

Autophagy is an evolutionarily conserved process utilized by most organisms to clear cellular damage and recycle building blocks for energy production. In this chapter, we emphasize the importance of genetic model organisms, including yeast, nematodes, flies, and mammals in the discovery and understanding of the autophagy process. We highlight the important roles of autophagy in aging, stress tolerance, neuronal health, organismal development, and pathogen resistance in invertebrate and vertebrate model organisms. We provide examples on how the same autophagy‐related pathways that increase stress response and longevity in lower organisms could be utilized by cancer cells to survive harsh microenvironments, proliferate, and metastasize, with emphasis on the dual role of autophagy in cancer: an antitumorigenic or a protumorigenic process

Seventh BHD international symposium: recent scientific and clinical advancement.

The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients' experiences living with this malady

HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain.

BACKGROUND: The HD-PTP protein has been described as a tumor suppressor candidate and based on its amino acid sequence, categorized as a classical non-transmembrane protein tyrosine phosphatase (PTP). To date, no HD-PTP phosphorylated substrate has been identified and controversial results concerning its catalytic activity have been recently reported. METHODOLOGY AND RESULTS: Here we report a rigorous enzymatic analysis demonstrating that the HD-PTP protein does not harbor tyrosine phosphatase or lipid phosphatase activity using the highly sensitive DiFMUP substrate and a panel of different phosphatidylinositol phosphates. We found that HD-PTP tyrosine phosphatase inactivity is caused by an evolutionary conserved amino acid divergence of a key residue located in the HD-PTP phosphatase domain since its back mutation is sufficient to restore the HD-PTP tyrosine phosphatase activity. Moreover, in agreement with a tumor suppressor activity, HD-PTP expression leads to colony growth reduction in human cancer cell lines, independently of its catalytic PTP activity status. CONCLUSION: In summary, we demonstrate that HD-PTP is a catalytically inactive protein tyrosine phosphatase. As such, we identify one residue involved in its inactivation and show that its colony growth reduction activity is independent of its PTP activity status in human cancer cell lines

Regulation of Translation by TOR, eIF4E and eIF2 alpha in Plants:Current Knowledge, Challenges and Future Perspectives

An important step in eukaryotic gene expression is the synthesis of proteins from mRNA, a process classically divided into three stages, initiation, elongation, and termination. Translation is a precisely regulated and conserved process in eukaryotes. The presence of plant-specific translation initiation factors and the lack of well-known translational regulatory pathways in this kingdom nonetheless indicate how a globally conserved process can diversify among organisms. The control of protein translation is a central aspect of plant development and adaptation to environmental stress, but the mechanisms are still poorly understood. Here we discuss current knowledge of the principal mechanisms that regulate translation initiation in plants, with special attention to the singularities of this eukaryotic kingdom. In addition, we highlight the major recent breakthroughs in the field and the main challenges to address in the coming years

Mutational analysis of the mammalian translation initiation factor eIF-4A

eIF-4A is a eukaryotic translation initiation factor and DEAD box RNA helicase that is thought to be responsible for the melting of secondary structure in the 5$sp prime$ untranslated region of messenger RNAs to facilitate ribosome binding. A mutational analysis of eIF-4A revealed that the ATPase A motif (AXXXXGKT) is involved in ATP binding, the ATPase B motif (DEAD) is implicated in ATP hydrolysis, the SAT region is essential for RNA unwinding, and the HRIGRXXR region is required for ATP hydrolysis-dependent RNA binding. Furthermore, defective eIF-4A mutants exhibit a strong dominant negative effect on in vitro translation of several mRNAs, including those translated by a cap-independent internal initiation mechanism. It is demonstrated that eIF-4A functions primarily as a subunit of eIF-4F, and singular eIF-4A is required to recycle through the eIF-4F during translation. Accordingly, eIF-4F appears to be required for cap-dependent and internal initiation of translation

Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin

The cellular function of folliculin (FLCN) is a mystery that still needs to be solved. It is known that mutation of FLCN can predispose Birt–Hogg–Dubé (BHD) patient’s to renal cell carcinoma , renal and lung cysts, as well as skin fibrofolliculomas. FLCN has been classed as a tumour suppressor, but it is probable that cystic and the skin manifestations do not occur as a consequence of FLCN loss of heterozygosity. Discovery that FLCN is a direct substrate of AMP dependent protein kinase (AMPK) placed FLCN on the cell signalling map, downstream of AMPK. This breakthrough suggested that FLCN might be involved in cell energy homeostasis. Over these more recent years, BHD research has become much more complicated and interesting from a cell signalling perspective. Folliculin has been linked to numerous cell pathways that are known to cause cancer, involving cell growth, metabolism, cell adhesion, cell motility, cytokinesis, and cell survival. The collective evidence implies that FLCN may have a broader housekeeping role in the cell. Of particular importance, FLCN was recently been reported to have guanine exchange factor activity towards the small G protein Rab35 and implicates FLCN in vesicular trafficking and/or membrane sorting. This newer discovery will undoubtedly help in the continued challenge of solving the signalling puzzle that shrouds FLCN function

HCV NS2/3 protease: a future antiviral drug target?

Current HCV therapy presents many side effects, is inadequate in treating all patients infected with the disease, and it is likely that future therapy will involve the specific targeting of multiple viral enzymes. The HCV NS2/3 protease is a dimeric autocatalytic protease that cleaves the viral polyprotein between NS2 and NS3. NS2/3 cleavage has been shown to be absolutely required for genome replication and viral infectivity in a chimpanzee and, therefore, NS2/3 has been suggested to be a promising target for future HCV drug development. This article focuses on the characterization of NS2/3 processing, the methods developed and progress achieved towards the generation of NS2/3 cleavage inhibitors. The challenges involved in developing active site inhibitors of this enzyme, as well as alternative approaches to inhibiting HCV replication through the NS2/3 and NS2 proteins, are also discussed. </jats:p