Alternative splice variant of actinin-4 in small cell lung cancer

Honda, Kazufumi; Yamada, Tesshi; Seike, Masahiro; Hayashida, Yasuharu; Idogawa, Masashi; Kondo, Tadashi; Ino, Yoshinori; Hirohashi, Setsuo

doi:10.1038/sj.onc.1207652

Cited by 50 publications

(39 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the precise roles of ␣-actinin 4 in tumorigenesis are controversial, ␣-actinin 4 has been proposed to play a role in cell motility and cancer invasion (4,(22)(23)(24)(25). Our findings that ␣-actinin 4 has a role in transcriptional regulation provides a possible, additional mechanism by which mutant ␣-actinin 4 might contribute to the pathogenesis of these diseases.…”

Section: Discussionmentioning

confidence: 81%

α-Actinin 4 Potentiates Myocyte Enhancer Factor-2 Transcription Activity by Antagonizing Histone Deacetylase 7

Chakraborty

Reineke

Lam

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Histone deacetylase 7 (HDAC7) is a member of class IIaHDACs that regulate myocyte enhancer factor-2 (MEF2)-mediated transcription and participate in multiple cellular processes such as T cell apoptosis. We have identified ␣-actinin 1 and 4 as class IIa HDAC-interacting proteins. The interaction domains are mapped to C terminus of ␣-actinin 4 and amino acids 72-172 of HDAC7. A point mutation in HDAC7 that disrupts its association with MEF2A also disrupts its association with ␣-actinin 4, indicating that MEF2A and ␣-actinin 4 binding sites largely overlap. We have also isolated a novel splice variant of ␣-actinin 4 that is predominantly localized in the nucleus, a pattern distinct from the full-length ␣-actinin 4, which is primarily distributed in the cytoplasm and plasma membrane. Using small interfering RNA, chromatin immunoprecipitation, and transient transfection assays, we show that ␣-actinin 4 potentiates expression of TAF55, a putative MEF2 target gene. Loss of MEF2A interaction correlates with loss of the ability of ␣-actinin 4 to potentiate TAF55 promoter activity. Ectopic expression of ␣-actinin 4, but not the mutant defective in MEF2A association, leads to disruption of HDAC7⅐MEF2A association and enhancement of MEF2-mediated transcription. Taken together, we have identified a novel mechanism by which HDAC7 activity is negatively regulated and uncovered a previously unknown function of ␣-actinin 4.

show abstract

Section: Discussionmentioning

confidence: 81%

α-Actinin 4 Potentiates Myocyte Enhancer Factor-2 Transcription Activity by Antagonizing Histone Deacetylase 7

Chakraborty

Reineke

Lam

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…1E). The alternative exon is nearly identical to the exon it replaces and changes just three amino acids in the resulting protein, which has a higher affinity for actin and an altered subcellular location as a result; therefore, this could be the cause of the abnormal cytoskeleton found in small cell lung cancer (21). Cancer is a complex integrated process involving signals that come from the extracellular matrix to the nucleus and back again; therefore, for simplicity, the following examples of alternative splicing in cancer are categorised according to their relatively well-characterized subcellular locations, whether it be nuclear, cytoplasmic, transmembrane, or extracellular.…”

Section: Alternative Splicing In Cancermentioning

confidence: 99%

Aberrant and Alternative Splicing in Cancer

2004

View full text Add to dashboard Cite

Pre-mRNA splicing is a sophisticated and ubiquitous nuclear process, which is a natural source of cancer-causing errors in gene expression. Intronic splice site mutations of tumor suppressor genes often cause exon-skipping events that truncate proteins just like classical nonsense mutations. Also, many studies over the last 20 years have reported cancerspecific alternative splicing in the absence of genomic mutations. Affected proteins include transcription factors, cell signal transducers, and components of the extracellular matrix. Antibodies against alternatively spliced products on cancer cells are currently in clinical trials, and competitive reverse transcription-PCR across regions of alternative splicing is being used as a simple diagnostic test. As well as being associated with cancer, the nature of the alternative gene products is usually consistent with an active role in cancer; therefore, the alternative splicing process itself is a potential target for gene therapy. Splice Site Mutations Can Cause Aberrant Splicing and CancerDefects in mRNA splicing are an important cause of disease (1-3). The most common form of splicing defects are genomic splice site point mutations, and a recent survey found 29 different p53 splice site mutations in Ͼ12 different types of cancer (4). Ninety-nine percent of all exons are flanked by the intronic dinucleotides GT and AG at the 5Ј and 3Ј splice sites respectively, and mutation of these sites usually causes exclusion of the adjacent exon (Fig. 1A), although sometimes splice site mutations have even more drastic consequences, e.g., double exon skipping in MLH1 in hereditary nonpolyposis colorectal cancer (5). More than half of all exon deletions lead to truncation of the encoded protein and as such, mutations in tumor suppressor genes at the invariant intronic dinucleotide can act much as classical nonsense mutations. For example a GT to AT 5Ј splice site mutation in hSNF5 causes deletion of exon 7, a frame shift, and a truncated reading frame, and this causes infant brain tumors when a "second hit" is provided at the wild-type allele by a deletion (6). Similarly a 3Ј splice site AG to AT mutation caused constitutive loss of exon 4 of the APC gene in colorectal to liver metastases, where the wild-type allele was deleted (ref. 7; Fig. 1A).Mutations in the less conserved splice site consensus away from the invariant dinucleotides tend to lead to partial aberrant splicing, often with a relatively mild phenotype. For example, the most common pathogenic mutation of the ATM gene is linked to breast cancer but is incompletely penetrant and is thought to have originated in Palaeolithic times. This is a mutation at the sixth position of an intron that causes a proportion of transcripts to skip an exon and to be frame shifted leading to a truncated protein (8). The polypyrimidine tract signal associated with the 3Ј splice site is another hot spot for mutation (Fig. 1A). An intronic mutation 11 nucleotides upstream of a 3Ј splice site in MLH1 knocks out an exon, and this ...

show abstract

“…siRNAs targeted against ACTN4 (siACTN4, UCA ACG AAC UGG ACU ACU AUU), ACTN1 (siACTN1, CAC UUA UCU UCG ACA AUA A), or non-related control (siNR, AUU CUA UCA CUA GCG UGA CUU) were from Qiagen (Valencia, CA). Enhanced green fluorescent protein-tagged human ACTN4 (ACTN4-GFP) cDNA, previously described (38,39), was a kind gift of Dr. Kazufumi Honda (National Cancer Center Research Institute, Tokyo, Japan). Enhanced green fluorescent protein-tagged C-terminal K-Ras tail (K-Ras tail-GFP) cDNA, as in Yeung et al (40), was a kind gift of Dr. Sergio Grinstein (Hospital for Sick Children, Toronto).…”

Section: Methodsmentioning

confidence: 99%

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

Talior-Volodarsky

Randhawa

Zaid

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Insulin induces GLUT4 translocation to the muscle cell surface. Using differential amino acid labeling and mass spectrometry, we observed insulin-dependent co-precipitation of actinin-4 (ACTN4) with GLUT4 (Foster, L. J., Rudich, A., Talior, I., Patel, N., Huang, X., Furtado, L. M., Bilan, P. J., Mann, M., and Klip, A. (2006) J. Proteome Res. 5, 64 -75). ACTN4 links F-actin to membrane proteins, and actin dynamics are essential for GLUT4 translocation. We hypothesized that ACTN4 may contribute to insulin-regulated GLUT4 traffic. In L6 muscle cells insulin, but not platelet-derived growth factor, increased co-precipitation of ACTN4 with GLUT4. Small interfering RNA-mediated ACTN4 knockdown abolished the gain in surface-exposed GLUT4 elicited by insulin but not by platelet-derived growth factor, membrane depolarization, or mitochondrial uncoupling. In contrast, knockdown of ␣-actinin-1 (ACTN1) did not prevent GLUT4 translocation by insulin. GLUT4 colocalized with ACTN4 along the insulin-induced cortical actin mesh and ACTN4 knockdown prevented GLUT4-actin colocalization without impeding actin remodeling or Akt phosphorylation, maintaining GLUT4 in a tight perinuclear location. We propose that ACTN4 contributes to GLUT4 traffic, likely by tethering GLUT4 vesicles to the cortical actin cytoskeleton. Insulin-regulated glucose transporter 4 (GLUT4)4 is a member of the SLC2A facilitative glucose transporter family (2) and is responsible for glucose entry into muscle and fat tissues (3-5). GLUT4 continuously cycles to/from the cell membrane through a series of endosomal compartments. In response to insulin there is a rapid increase in the steady-state level of GLUT4 at the cell surface, at the expense of intracellular pools (6 -9). This process is defective in insulin resistance and type 2 diabetes (10 -12). Stimuli other than insulin such as muscle contraction, depolarization, or hypoxia also increase surface GLUT4 (13-16). Whereas insulin largely increases the exocytic arm of GLUT4 cycling (17), hypoxia or membrane depolarization preferentially reduce GLUT4 endocytosis in muscle cells (16,18,19). Moreover, although insulin-dependent GLUT4 translocation requires dynamic remodeling of filamentous actin (20 -23), the gain in surface GLUT4 elicited by plateletderived growth factor (PDGF), depolarization, or mitochondrial uncouplers is independent of actin dynamics (24 -26).Intensive research has recently focused on identifying the individual mechanisms participating in GLUT4 traffic and the specific events regulated by insulin (27)(28)(29)(30)(31). Hypothesizing that GLUT4 traffic may be regulated by interaction with partner proteins, it is of fundamental and clinical interest to identify such proteins. Accordingly, we recently applied the novel SILAC (stable isotope labeling by amino acids in cell culture) approach (32) to search for proteins that associate with GLUT4 in an insulin-regulated manner (1). The study took advantage of the stable expression in L6 muscle cells of GLUT4 encoding an myc tag that faces the extrace...

show abstract

Alternative splice variant of actinin-4 in small cell lung cancer

Cited by 50 publications

References 14 publications

α-Actinin 4 Potentiates Myocyte Enhancer Factor-2 Transcription Activity by Antagonizing Histone Deacetylase 7

α-Actinin 4 Potentiates Myocyte Enhancer Factor-2 Transcription Activity by Antagonizing Histone Deacetylase 7

Aberrant and Alternative Splicing in Cancer

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

Contact Info

Product

Resources

About