Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival ...

/pdf/mechanisms-of-cancer-cachexia-26gc7sv3fx.pdf

Mechanisms of Cancer Cachexia

http://www.linkgroup.hu/docs/pcs/98pharmther.pdf

The 90-kDa molecular chaperone family : structure, function, and clinical applications. A comprehensive review

The 90-kDa molecular chaperone family (which comprises, among other proteins, the 90- kDa heat-shock protein, hsp90 and the 94-kDa glucose-regulated protein, grp94, major molecular chaperones of the cytosol and of the endoplasmic reticulum, respectively) has become an increasingly active subject of research in the past couple of years. These ubiquitous, well-conserved proteins account for 1-2% of all cellular proteins in most cells. However, their precise function is still far from being elucidated. Their involvement in the aetiology of several autoimmune diseases, in various infections, in recognition of malignant cells, and in antigen-presentation already demonstrates the essential role they likely will play in clinical practice of the next decade. The present review summarizes our current knowledge about the cellular functions, expression, and clinical implications of the 90-kDa molecular chaperone family and some approaches for future research. pharmacol. ther. 79(2):129-168, 1998. © 1998 Elsevier Science Inc.

/pdf/associate-editor-d-shugar-the-90-kda-molecular-chaperone-42hs4t0kau.pdf

Associate Editor: D. Shugar The 90-kDa Molecular Chaperone Family: Structure, Function, and Clinical Applications. A Comprehensive Review

Signaling through mammalian target of rapamycin (mTOR) is activated by amino acids, insulin, and growth factors, and impaired by nutrient or energy deficiency. mTOR plays key roles in cell physiology. mTOR regulates numerous components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves.

The mTOR pathway in the control of protein synthesis.

https://mmbr.asm.org/content/mmbr/56/2/291.full.pdf

Mechanism and regulation of eukaryotic protein synthesis.

The effect of phosphorylation on the functional activity of eukaryotic elongation factor 2 (eEF-2) was studied using a purified phosphorylated factor. The modified factor was unable to stimulate protein synthesis in an eEF-2-dependent rabbit reticulocyte lysate. The functional alteration was further analyzed by measuring the effects of phosphorylation on the ability of the factor to catalyse the ribosome-dependent hydrolysis of GTP. Kinetic analysis showed that both phosphorylated and unmodified factor was able to hydrolyse GTP with approximately the same maximum rate, indicating that the rate of nucleotide exchange was not impaired by the modification. However, the phosphorylated factor showed a marked reduction in the second-order rate constant, suggesting that the phosphorylation interfered with ribosome · eEF-2 complex formation by reducing the affinity of eEF-2 for the ribosome. This assumption was confirmed by direct measurements of the dissociation constants for the ribosomal complexes containing unmodified and phosphorylated eEF-2.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1990.tb19169.x

Functional properties of phosphorylated elongation factor 2

Phosphorylation regulates the activity of the eEF-2-specific Ca(2+)- and calmodulin-dependent protein kinase III.

Increased activity of the eEF-2 specific, Ca2+ and calmodulin dependent protein kinase III during the S-phase in Ehrlich ascites cells.

The Ca2+ - and calmodulin-dependent protein kinase III, which specifically phosphorylates the eukaryotic elongation factor 2 (eEF-2), has been purified to apparent homogeneity from the post-ribosomal fraction of rabbit reticulocytes by an efficient four-step method. The method results in a more than 4000-fold purification of the enzyme. SDS-gel electrophoresis showed that the purified kinase contained only one polypeptide with the apparent molecular mass of 90 kDa. The kinase activity was associated with the 90-kDa protein as shown by analyzing the phosphorylating activity of SDS gel electrophoretically purified protein electroblotted to nitrocellulose membranes. The purified kinase was dependent on Ca2+, Mg2+ and calmodulin for activity. Kinetic analysis of the phosphorylation reaction indicates that the turnover number of the kinase was approximately 1 s−1. The Km for the two substrates ATP and eEF-2 was calculated to be approximately 100 μM and 10 μM, respectively. The activity of the kinase was competitively inhibited by cAMP. The inhibition constant Ki (0.5 mM) was found to be in the same order of magnitude as that calculated for the competitive product inhibition caused by ADP. GTP was ten-times less efficient as competitor, indicating that the kinase had a preference for adenosine nucleotides. Phosphorylation of eEF-2 did not interfere with the diphtheria-toxin-catalysed ADP-ribosylation of the factor nor did ADP-ribosylation inhibit phosphorylation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1991.tb15716.x

Kinetic characterisation of the enzymatic activity of the eEF‐2‐specific Ca2+‐ and calmodulin‐dependent proteinkinase III purified from rabbit reticulocytes

Ulf Carlberg

Papers

Functional properties of phosphorylated elongation factor 2

Phosphorylation regulates the activity of the eEF-2-specific Ca(2+)- and calmodulin-dependent protein kinase III.

Increased activity of the eEF-2 specific, Ca2+ and calmodulin dependent protein kinase III during the S-phase in Ehrlich ascites cells.

Kinetic characterisation of the enzymatic activity of the eEF‐2‐specific Ca2+‐ and calmodulin‐dependent proteinkinase III purified from rabbit reticulocytes