Distribution and interrelationship of ubiquitin proteasome pathway component activities and ubiquitin pools in various porcine tissues

The ubiquitin-proteasome pathway fulfills major biological functions, but its physiologic tissue distribution and the interrelationship between pathway component activities and ubiquitin pools are unknown. Therefore, we analyzed free and conjugated ubiquitin, ubiquitin-protein ligation rates (UbPL) and chymotryptic- and tryptic-like proteasome peptidase activities in porcine skeletal muscle, heart, lung, liver, spleen and kidney (n=5 each). There were considerable differences between tissues (p<0.05 for all parameters). Lung and spleen showed high levels of free and conjugated ubiquitin and high UbPL. Proteasome activities were highest in kidney and heart. There were linear relationships between tryptic-like and chymotryptic-like proteasome peptidase activities (r(2) = 0.624, p<0.001) and between free and conjugated ubiquitin tissue levels (r(2) = 0.623, p<0.001). Tissue levels of free and conjugated ubiquitin correlated linear with UbPL (p<0.005), but they were not correlated with proteasome peptidase activities. The results suggest that tissue ubiquitin pools are tightly regulated and indicate a constant proportion of conjugated ubiquitin. They further support the hypothesis that ubiquitin-protein ligase systems, and probably deubiquitylating enzymes, are key regulators of ubiquitin homeostasis. The detected differences are suggestive of tissue-specific roles of ubiquitin-proteasome pathway components. Besides the known importance of the ubiquitin proteasome pathway in heart, kidney and the immune system, the results suggest the lung as another organ in which ubiquitin proteasome pathway components may also significantly contribute to disease processes.

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Mergla K + channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway

The FASEB Journal ◽

10.1096/fj.05-5350fje ◽

2006 ◽

Vol 20 (9) ◽

pp. 1531-1533 ◽

Cited By ~ 16

Author(s):

Xun Wang ◽

Gregory H. Hockerman ◽

Henry W. Green ◽

Charles F. Babbs ◽

Sulma I. Mohammad ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

K Channel ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

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Skeletal muscle proteolysis is associated with sympathetic activation and TNF-α-ubiquitin-proteasome pathway in liver cirrhotic rats

Journal of Gastroenterology and Hepatology ◽

10.1111/jgh.13159 ◽

2016 ◽

Vol 31 (4) ◽

pp. 890-896 ◽

Cited By ~ 8

Author(s):

Shih-Yi Lin ◽

Ya-Yu Wang ◽

Yu-Han Chuang ◽

Chun-Jung Chen

Keyword(s):

Skeletal Muscle ◽

Sympathetic Activation ◽

Ubiquitin Proteasome Pathway ◽

Tnf Α ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

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E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors

Nuclear Receptor Signaling ◽

10.1621/nrs.06006 ◽

2008 ◽

Vol 6 (1) ◽

pp. nrs.06006 ◽

Cited By ~ 56

Author(s):

Sivapriya Ramamoorthy ◽

Zafar Nawaz

Keyword(s):

Hormone Receptors ◽

Target Genes ◽

Steroid Hormone ◽

Enzymatic Activities ◽

Steroid Hormone Receptors ◽

Dual Function ◽

Biological Functions ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.

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Mechanisms of Cancer Cachexia

Physiological Reviews ◽

10.1152/physrev.00016.2008 ◽

2009 ◽

Vol 89 (2) ◽

pp. 381-410 ◽

Cited By ~ 672

Author(s):

Michael J. Tisdale

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Adipose Tissue ◽

Protein Degradation ◽

Initiation Factor ◽

Tissue Loss ◽

Α Subunit ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

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 time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the α-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFκB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-α, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.

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