TRIM28
Transcription intermediary factor 1-beta (TIF1-beta) (E3 SUMO-protein ligase TRIM28) (EC 2.3.2.27) (KRAB-associated protein 1) (KAP-1) (KRAB-interacting protein 1) (KRIP-1) (Nuclear corepressor KAP-1) (RING finger protein 96) (RING-type E3 ubiquitin transferase TIF1-beta) (Tripartite motif-containing protein 28) [KAP1] [RNF96] [TIF1B]
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Alzheimer's and Parkinson's disease are late onset neurodegenerative diseases that will require therapy over decades to mitigate the effects of disease-driving proteins such tau and α-synuclein (α-Syn). Previously we found that TRIM28 regulates the levels and toxicity of α-Syn and tau (<xref ref-type="bibr" rid="bib21">Rousseaux et al., 2016</xref>). However, it was not clear how TRIM28 regulates α-Syn and it was not known if its chronic inhibition later in life was safe. Here, we show that TRIM28 may regulate α-Syn and tau levels via SUMOylation, and that genetic suppression of Trim28 in adult mice is compatible with life. We were surprised to see that mice lacking Trim28 in adulthood do not exhibit behavioral or pathological phenotypes, and importantly, adult reduction of TRIM28 results in a decrease of α-Syn and tau levels. These results suggest that deleterious effects from TRIM28 depletion are limited to development and that its inhibition adulthood provides a potential path for modulating α-Syn and tau levels.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Behavior, Animal
- Biocatalysis
- Brain
- Gene Deletion
- Homeostasis
- Iron
- Mice, Inbred C57BL
- Mice, Knockout
- Protein Stability
- Sumoylation
- Tripartite Motif-Containing Protein 28
- alpha-Synuclein
- tau Proteins
Keywords
- Alzheimer's disease
- Parkinson's disease
- Tau
- alpha-Synuclein
- dosage sensitivity
- human
- mouse
- neuroscience
- safety
Hepatocellular carcinoma (HCC) represents the fifth-most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28 mice display sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28 -associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge. This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer-prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017;66:235-251).
MeSH Terms
- Aging
- Animals
- Carcinogenesis
- Carcinoma, Hepatocellular
- Diet, High-Fat
- Disease Models, Animal
- Epigenomics
- Female
- Genomic Instability
- Liver Neoplasms
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Oxidative Stress
- Phenotype
- Random Allocation
- Repressor Proteins
- Risk Assessment
- Risk Factors
- Tripartite Motif-Containing Protein 28