Characterization of a new human isoform of the enigma homolog family specifically expressed in skeletal muscle

Niederländer, Nicolas J.; Fayein, N.A.; Auffray, Charles; Pomiès, Pascal

doi:10.1016/j.bbrc.2004.10.178

Cited by 29 publications

(31 citation statements)

References 18 publications

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“…Although we have been focused primarily on the functional interaction between ENH and Id2 in neural cells, the ability of ENH to bind other Id proteins combined with its participation in differentiation of other tissue types (e.g., muscle) suggests that ENH may be a general inducer of differentiation through binding and cytoplasmic sequestration of Id proteins. Recently, additional isoforms of ENH (ENH2, ENH3, and ENH4) have been identified in human and mouse muscle tissues (19,38). These isoforms lack the three LIM domains and resemble the ENH␦LIM mutant tested by us in Fig.…”

Section: Discussionmentioning

confidence: 64%

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The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Lasorella

Iavarone

2006

Proc. Natl. Acad. Sci. U.S.A.

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Id2 is a natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein. Active Id2 prevents differentiation and promotes cell-cycle progression and tumorigenesis in the nervous system. A key event that regulates Id2 activity during differentiation is translocation from the nucleus to the cytoplasm. Here we show that the actin-associated protein enigma homolog (ENH) is a cytoplasmic retention factor for Id2. ENH contains three LIM domains, which bind to the helixloop-helix domain of Id proteins in vitro and in vivo. ENH is up-regulated during neural differentiation, and its ectopic expression in neuroblastoma cells leads to translocation of Id2 from the nucleus to the cytoplasm, with consequent inactivation of transcriptional and cell-cycle-promoting functions of Id2. Conversely, silencing of ENH by RNA interference prevents cytoplasmic relocation of Id2 in neuroblastoma cells differentiated with retinoic acid. Finally, the differentiated neural crest-derived tumor ganglioneuroblastoma coexpresses Id2 and ENH in the cytoplasm of ganglionic cells. These data indicate that ENH contributes to differentiation of the nervous system through cytoplasmic sequestration of Id2. They also suggest that ENH is a restraining factor of the oncogenic activity of Id proteins in neural tumors.differentiation ͉ enigma homolog ͉ Id proteins ͉ neural cancer I d2 is one of the four members of the Id protein family, a group of proteins known as inhibitor of differentiation (1, 2). Id2 lies at the center of a molecular network including the retinoblastoma (Rb) tumor suppressor protein and the basic helix-loop-helix (bHLH) transcription factors, the best-known targets for inhibition by Id2 (3, 4). These connections probably operate in a variety of cell types, but our work has characterized them in the nervous system (5-7). In this tissue, overexpression of Id proteins inhibits differentiation whereas ablation of Id genes induces premature differentiation of various neural cell types in vitro and in vivo (8-10). As physiologic regulator of Id2, Rb cooperates with bHLH transcription factors to promote cell-cycle arrest and differentiation in the developing brain. This pathway is subverted in tumor cells. Malignant transformation in the central and peripheral nervous system coincides with frequent elevation of Id2, a process typically implemented by the activation of oncoproteins such as Myc and Ews-Fli1 that up-regulate Id2 gene transcription, (6,7,11,12). The aberrant accumulation of Id2 contributes to uncontrolled proliferation and neoangiogenesis, two hallmarks of neural cancer (13).There is general agreement with the notion that differentiation of a variety of cell types requires elimination of Id function. However, the mechanisms by which the signaling pathways initiating differentiation in the nervous system inactivate Id proteins are unknown. Although Id are viewed mainly as nuclear proteins, recent papers reported that relocation of Id proteins to the cytoplasm is an effective...

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Section: Discussionmentioning

confidence: 64%

“…1 A and B. Based on our results, we conclude that the alternative ENH isoforms are unable to bind Id2, a property that might contribute to a potential dominant-negative activity toward full-length ENH (ENH1) in vivo (19,38).…”

Section: Discussionmentioning

confidence: 64%

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Lasorella

Iavarone

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…At the same time, immunolocalization studies have shown that not all known Z-disc proteins are involved in this process [10,20]. Indeed, our proteomic data show that the two Z-disc proteins α-actinin-3 and the α-actinin binding partner PDZ and LIM domain protein 5 [34] are significantly decreased in aggregate samples of desminopathy patients. These and many other results derived from proteomic analysis provide new information about Z-disc protein involvement in the pathogenesis of desminopathy.…”

Section: Discussionmentioning

confidence: 78%

Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy

Maerkens

Kley

Olivé

et al. 2013

Journal of Proteomics

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Desminopathy is a subtype of myofibrillar myopathy caused by desmin mutations and characterized by protein aggregates accumulating in muscle fibers. The aim of this study was to assess the protein composition of these aggregates. Aggregates and intact myofiber sections were obtained from skeletal muscle biopsies of five desminopathy patients by laser microdissection and analyzed by a label-free spectral count-based proteomic approach. We identified 397 proteins with 22 showing significantly higher spectral indices in aggregates (ratio >1.8, p < 0.05). Fifteen of these proteins not previously reported as specific aggregate components provide new insights regarding pathomechanisms of desminopathy. Results of proteomic analysis were supported by immunolocalization studies and parallel reaction monitoring. Three mutant desmin variants were detected directly on the protein level as components of the aggregates, suggesting their direct involvement in aggregate-formation and demonstrating for the first time that proteomic analysis can be used for direct identification of a disease-causing mutation in myofibrillar myopathy. Comparison of the proteomic results in desminopathy with our previous analysis of aggregate composition in filaminopathy, another myofibrillar myopathy subtype, allows to determine subtype-specific proteomic profile that facilitates identification of the specific disorder.

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“…A group of PDZ-LIM proteins localize at the muscle Z-disc and interact with α-actinin. This group is composed of Z-band alternatively spliced PDZcontaining protein (ZASP/Cypher/Oracle) [3][4][5], actinin-associated LIM protein (ALP) [6,7], C-terminal LIM domain protein (CLP36/Elfin/hCLIM1) [8][9][10][11][12][13], and Enigma homology protein (ENH) [14,15]. Also Enigma localizes at the Z-lines [16], but there is no evidence of the interaction to α-actinin so far.…”

Section: Introductionmentioning

confidence: 99%

Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with α-actinin—Analysis of patient mutations

Klaavuniemi

Ylänne

2006

Experimental Cell Research

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Characterization of a new human isoform of the enigma homolog family specifically expressed in skeletal muscle

Cited by 29 publications

References 18 publications

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy

Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with α-actinin—Analysis of patient mutations

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