Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Inhibin is a secreted tumor suppressor and an activin antagonist. Inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance and die of a cachexia-like syndrome due to increased activin signaling. Because Sma and Mad-related protein (SMAD)2 and SMAD3 transduce activin signals in vitro, we attempted to define the role of SMAD3 in gonadal tumorigenesis and the wasting syndrome by generating inhibin alpha and Smad3 double mutant mice. Inhibin alpha and Smad3 double homozygous males were protected from early tumorigenesis and the usual weight loss and death. Approximately 90% of these males survived to 26 wk in contrast to 95% of inhibin-deficient males, which develop bilateral testicular tumors and die of the wasting syndrome by 12 wk. Testicular tumors were either absent or unilaterally slow growing and less hemorrhagic in the majority of double-knockout males. In contrast, development of the ovarian tumors and wasting syndrome was delayed, but still occurred, in the majority of the double-knockout females by 26 wk. In double mutant females, tumor development was accompanied by typical activin-induced pathological changes. In summary, we identify an important function of SMAD3 in gonadal tumorigenesis in both sexes. However, this effect is significantly more pronounced in the male, indicating that SMAD3 is the primary transducer of male gonadal tumorigenesis, whereas SMAD3 potentially overlaps with SMAD2 function in the ovary. Moreover, the activin-induced cachexia syndrome is potentially mediated through both SMAD2 and SMAD3 or only through SMAD2 in the liver and stomach. These studies identify sexually dimorphic functions of SMAD3 in gonadal tumorigenesis.
Mol Endocrinol 2007 Oct
PMID:SMAD3 regulates gonadal tumorigenesis. 1759 16

Progressive muscle wasting is a central feature of cancer-related cachexia and has been recognized as a determinant of poor prognosis and quality of life. However, until now, no easily assessable clinical marker exists that allows to predict or to track muscle wasting. The present study evaluated the potential of myoglobin (MG) plasma levels to indicate wasting of large locomotor muscles and, moreover, to reflect the loss of MG-rich fiber types, which are most relevant for daily performance. In 17 cancer-cachectic patients (weight loss 22%) and 27 age- and gender-matched healthy controls, we determined plasma levels of MG and creatine kinase (CK), maximal quadriceps muscle cross-sectional area (CSA) by magnetic resonance imaging, muscle morphology and fiber composition in biopsies from the vastus lateralis muscle, body cell mass (BCM) by impedance technique as well as maximal oxygen uptake (VO(2)max). In cachectic patients, plasma MG, muscle CSA, BCM, and VO(2)max were 30-35% below control levels. MG showed a significant positive correlation to total muscle CSA (r = 0.65, p < 0.001) and to the CSA fraction formed by type 1 and 2a fibers (r = 0.80, p < 0.001). However, when adjusted for body height and age by multiple regression, MG yielded a largely improved prediction of total CSA (multiple r = 0.83, p < 0.001) and of fiber type 1 and 2a CSA (multiple r = 0.89, p < 0.001). The correlations between CK and these muscle parameters were weaker, and elevated CK values were observed in 20% of control subjects despite a prior abstinence from exercise for 5 days. In conclusion, plasma MG, when adjusted for anthropometric parameters unaffected by weight, may be considered as a novel marker of muscle mass (CSA) indicating best the mass of MG-rich type 1 and 2a fibers as well as VO(2)max as an important functional readout. CK plasma levels appear to be less reliable because prolonged increases are observed in even subclinical myopathies or after exercise. Notably, cancer-related muscle wasting was not associated with increases in plasma MG or CK in this study.
J Mol Med (Berl) 2007 Aug
PMID:Myoglobin plasma level related to muscle mass and fiber composition: a clinical marker of muscle wasting? 1760 53

Inhibin is a secreted tumor suppressor, and inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin-deficient mice die of a severe wasting syndrome due to increased activin signaling through activin receptor type II. The current study was designed to assess the in vivo effects of an activin antagonist, a chimeric activin receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate-buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of activins in the cachexia-like syndrome development and implicate activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII.
Mol Hum Reprod 2007 Sep
PMID:Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein. 1770 37

Ghrelin is a potent orexigenic peptide principally produced in the stomach by a distinct population of neuroendocrine cells in the oxyntic mucosa of the fundus. Exogenous ghrelin given as an intravenous infusion has been shown to increase caloric intake in patients with cancer cachexia. In this study, we hypothesized that elevated endogenous ghrelin, produced by increased neuroendocrine cell tumor burden, also exerts an orexigenic effect helping to maintain body mass index. To evaluate the effect of elevated endogenous ghrelin, 35 patients with neuroendocrine tumors were enrolled, assigning them to one of two groups depending on the presence of hepatic metastases. Following an overnight fast, serum was collected and sent for ghrelin measurement by an outside laboratory. The two groups were well matched for all other relevant clinical variables including subtype of tumor, primary location of tumor and tumor treatment history. Nearly all patients with hepatic metastases had elevated levels of ghrelin compared to the standard reference range given for matched controls. The presence of hepatic metastases was associated with significantly elevated ghrelin levels (p<0.05) and a greater mean body mass index. In addition, we report a positive correlation between serum ghrelin and total tumor surface area and between serum ghrelin and body mass index, suggesting that elevated endogenous ghrelin may be sufficient to overcome any partial ghrelin resistance typically seen in cancer cachexia. These results support the possibility that ghrelin is co-released from neuroendocrine tumors and exerts an orexigenic effect in these patients, helping to maintain their body mass index despite widely disseminated disease.
J Mol Neurosci 2007
PMID:Elevated serum ghrelin exerts an orexigenic effect that may maintain body mass index in patients with metastatic neuroendocrine tumors. 1795 31

Parafibromin, a transcription factor associated with the PAF complex, is encoded by the HRPT2 gene, mutations of which cause the hyperparathyroidism-jaw tumor syndrome (OMIM145001). To elucidate the function of parafibromin, we generated conventional and conditional Hrpt2 knockout mice and found that Hrpt2(-/-) mice were embryonic lethal by embryonic day 6.5 (E6.5). Controlled deletion of Hrpt2 after E8.5 resulted in apoptosis and growth retardation. Deletion of Hrpt2 in adult mice led to severe cachexia and death within 20 days. To explore the mechanism underlying the embryonic lethality and death of adult mice, mouse embryonic fibroblasts (MEFs) were cultured and Hrpt2 was deleted in vitro. Hrpt2(-/-) MEFs underwent apoptosis, while Hrpt2(+/+) and Hrpt2(+/-) MEFs grew normally. To study the mechanism of this apoptosis, Hrpt2(+/+) and Hrpt2(-/-) MEFs were used in cDNA microarray, semiquantitative reverse transcription-PCR, and chromatin immunoprecipitation assays to identify genes regulated by parafibromin. These revealed that Hrpt2 expression and the parafibromin/PAF complex directly regulate genes involved in cell growth and survival, including H19, Igf1, Igf2, Igfbp4, Hmga1, Hmga2, and Hmgcs2. Thus, our results show that expression of Hrpt2 and parafibromin is pivotal in mammalian development and survival in adults and that these functions are likely mediated by the transcriptional regulation of growth factors.
Mol Cell Biol 2008 May
PMID:Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice. 1821 49

Studies described in the recent literature support the idea that gene therapy can lead to genuine clinical benefits when mediated by plasmid delivery in conjunction with electroporation. Plasmid-mediated muscle-targeted gene transfer offers the potential of a cost-effective pharmaceutical-grade therapy delivered by simple intramuscular injection. This approach is particularly appropriate for modulating muscle and fat mass and their intrinsic properties, from treatment of conditions such as cachexia associated with chronic diseases, autoimmune diseases, e.g., myasthenia gravis, to stimulation or suppression of appetite, and further to in vivo manipulation of glucose metabolism and fat deposition in patients with diabetes, or to basic studies of muscle-specific transcription factors and their impact in development. Recent innovations, including in situ electroporation, enabling sustained systemic protein delivery within the therapeutic range, are reviewed. Translation of these advances to human clinical trials will enable muscle- and fat-targeted gene therapy to become a viable therapeutic alternative.
Methods Mol Biol 2008
PMID:Muscle and fat mass modulation in different clinical models. 1837 Feb 21

Zinc alpha 2-glycoprotein (ZAG) is a protein of interest because of its ability to play many important functions in the human body, including fertilization and lipid mobilization. After the discovery of this molecule, during the last 5 decades, various studies have been documented on its structure and functions, but still, it is considered as a protein with an unknown function. Its expression is regulated by glucocorticoids. Due to its high sequence homology with lipid-mobilizing factor and high expression in cancer cachexia, it is considered as a novel adipokine. On the other hand, structural organization and fold is similar to MHC class I antigen-presenting molecule; hence, ZAG may have a role in the expression of the immune response. The function of ZAG under physiologic and cancerous conditions remains mysterious but is considered as a tumor biomarker for various carcinomas. There are several unrelated functions that are attributed to ZAG, such as RNase activity, regulation of melanin production, hindering tumor proliferation, and transport of nephritic by-products. This article deals with the discussion of the major aspects of ZAG from its gene structure to function and metabolism.
Mol Cancer Res 2008 Jun
PMID:Zinc alpha 2-glycoprotein: a multidisciplinary protein. 1856 94

This review of androgen receptor (AR) coregulators, which also function as actin-binding proteins, intends to establish the connection between actin cytoskeletal components and androgen signaling, especially in skeletal muscle. In cellular and animal models, androgen activated AR modulates myoblasts proliferation, promotes sexual dimorphic muscle development, and alters muscle fiber type. In the clinical setting, administration of anabolic androgens can decrease cachexia and speed wound healing. During myogenesis and regeneration of skeletal muscle in embryo and adult, the membrane of myoblasts fuse and the actin cytoskeleton is rearranged to form an alignment with myosin to form myotubes then ultimately the myofibrils. Contraction of skeletal muscle promotes the growth of myocytes by coordinating signals from the neuromuscular junction to intra-myofibrils through costameres, the functional structure comprised of signal proteins closely associated with actin filaments and involved in muscular dystrophy. Therefore, the discovery of actin-binding proteins functioning as AR coregulators implies that androgen signaling is tightly regulated during the process of the development and regeneration of skeletal muscle. The search for selective androgen receptor modulators (SARM) that act precisely in skeletal muscle instead of other tissues could target the engineering of a SARM-AR complex that selectively recruits these coregulators.
J Steroid Biochem Mol Biol 2008 Sep
PMID:Actin associated proteins function as androgen receptor coregulators: an implication of androgen receptor's roles in skeletal muscle. 1859 Aug 22

DING proteins, identified mainly by their eponymous N-terminal sequences, are ubiquitous in living organisms. Amongst bacteria, they are common in pseudomonads, and have been characterised with respect to genetics and structure. They form part of a wider family of phosphate-binding proteins, with emerging roles in phosphate acquisition and pathogenicity. Many DING proteins have been isolated in eukaryotes, in which they have been associated with very diverse biological activities, often in the context of possible signalling roles. Disease states in which DING proteins have been implicated include rheumatoid arthritis, lithiasis, atherosclerosis, some tumours and tumour-associated cachexia, and bacterial and viral adherence. Complete genetic and structural characterisation of eukaryotic DING genes and proteins is still lacking, though the phosphate-binding site seems to be conserved. Whether as bacterial proteins related to bacterial pathogenicity, or as eukaryotic components of biochemical signalling systems, DING proteins require further study.
Cell Mol Life Sci 2009 Jul
PMID:For whom the bell tolls? DING proteins in health and disease. 1929 Apr 74

The tissue-specific expressions of creatine kinase (CK) isoforms are regulated by the coordinated action of various transcription factors. The myogenic differentiation factor D (MyoD) family of proteins and the myocyte-specific enhancer binding factor 2 family of transcription factors are important in regulating the muscle-specific expression of cytosolic muscle-type CK (MCK) and mitochondrial CKs. As reported in some related studies, TNF-alpha mediated degradation of MyoD and myogenin mRNA may lead to severe muscle wasting and cachexia, which is characterized by a low transcript level of MCK and myosin heavy chain proteins. In our previous study, we reported on a complete loss of total CK activity and expression when sarcoma was induced in mouse skeletal muscle (Patra et al. FEBS J. 275 (2008) 3236-3247). This study aimed at investigating the transcriptional cascade of CK down-regulation in carcinogen-induced sarcoma in mouse muscle. Both CK deficiency and enhanced nitric oxide synthase (NOS) were known to augment mitochondrial biogenesis, so we also explored the activation of the transcriptional cascade of mitochondrial biogenesis in this cancer. We observed the activation of the TNF-alpha-mediated nitric oxide production pathway with NFkappaB activation and concomitant degradation of MyoD and myogenin mRNA. Exploration of mitochondrial biogenesis revealed high cytochrome c oxidase activity and mitochondrial DNA content in sarcoma. The PGC-related co-activator seems to have a major role in regulating mitochondrial biogenesis by upregulating nuclear respiratory factors and mitochondrial transcription factor A. From the above findings, it can be concluded that severe muscle degeneration leads to CK down-regulation in sarcoma, and that the stimulation of mitochondrial biogenesis indicated a scenario representing both CK deficiency and NOS overexpression on the one hand, and altered bioenergetic profiling on the other.
Cell Mol Biol Lett 2009
PMID:The transcriptional cascade associated with creatine kinase down-regulation and mitochondrial biogenesis in mice sarcoma. 1934 76


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