Ubiquitin-Protein Ligases

Publication Title: 
Journal of Virology

Human papillomaviruses (HPVs) belonging to the Betapapillomavirus genus have recently been implicated in squamous cell carcinomas of the skin, though the mechanisms by which they initiate carcinogenesis are unclear. We show that human foreskin keratinocytes (HFKs) expressing several betapapillomavirus E6 (beta-E6) proteins display life span extension, but not to the extent seen in HFKs expressing HPV type 16 E6 (16E6). Additionally, we demonstrate that beta-E6 proteins can differentially activate telomerase.

Author(s): 
Bedard, Kristin M.
Underbrink, Michael P.
Howie, Heather L.
Galloway, Denise A.
Publication Title: 
PLoS genetics

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking.

Author(s): 
Kruegel, Undine
Robison, Brett
Dange, Thomas
Kahlert, G¸nther
Delaney, Joe R.
Kotireddy, Soumya
Tsuchiya, Mitsuhiro
Tsuchiyama, Scott
Murakami, Christopher J.
Schleit, Jennifer
Sutphin, George
Carr, Daniel
Tar, Krisztina
Dittmar, Gunnar
Kaeberlein, Matt
Kennedy, Brian K.
Schmidt, Marion
Publication Title: 
Molecular and Cellular Biology

SIRT3 is a member of the Sir2 family of NAD(+)-dependent protein deacetylases that promotes longevity in many organisms. The processed short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remain controversial. Our previous studies demonstrated that nuclear FL SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene.

Author(s): 
Iwahara, Toshinori
Bonasio, Roberto
Narendra, Varun
Reinberg, Danny
Publication Title: 
Gene

Previous studies have shown that polyphenols might be potent neuroprotective agents in Drosophila melanogaster wild type Canton-S acutely or chronically treated with paraquat (PQ), a selective toxin for elimination of dopaminergic (DAergic) neurons by oxidative stress (OS), as model of Parkinson's disease (PD).

Author(s): 
Bonilla-Ramirez, Leonardo
Jimenez-Del-Rio, Marlene
Velez-Pardo, Carlos
Publication Title: 
Molecular and Cellular Biology

The ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) regulates protein quality control, and CHIP deletion accelerates aging and reduces the life span in mice. Here, we reveal a mechanism for CHIP's influence on longevity by demonstrating that CHIP stabilizes the sirtuin family member SirT6, a lysine deacetylase/ADP ribosylase involved in DNA repair, metabolism, and longevity.

Author(s): 
Ronnebaum, Sarah M.
Wu, Yaxu
McDonough, Holly
Patterson, Cam
Publication Title: 
Cell Reports

Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting.

Author(s): 
Uno, Masaharu
Honjoh, Sakiko
Matsuda, Mitsuhiro
Hoshikawa, Haruka
Kishimoto, Saya
Yamamoto, Tomohito
Ebisuya, Miki
Yamamoto, Takuya
Matsumoto, Kunihiro
Nishida, Eisuke
Publication Title: 
Journal of Neurology, Neurosurgery, and Psychiatry

OBJECTIVES: Cerebellar haemangioblastoma occurs sporadically or as a component tumour of autosomal dominant von Hippel-Lindau disease. Biallelic inactivation of the VHL tumour suppressor gene, which is located on chromosome 3p, has been shown to be involved in the pathogenesis of both tumour entities. Mechanisms of VHL inactivation are intragenic mutations, mitotic recombination events, and hypermethylation of the promoter region.

Author(s): 
Gl‰sker, S.
Bender, B. U.
Apel, T. W.
van Velthoven, V.
Mulligan, L. M.
Zentner, J.
Neumann, H. P.
Publication Title: 
Journal of Neurology, Neurosurgery, and Psychiatry

The genetic analysis of common neurological disorders will be a difficult and protracted endeavour. Genetics is only one of many disciplines that will be required but it has already thrown considerable light on the aetiology of several major neurological disorders through the analysis of rare inherited subgroups. The identification of individual susceptibility genes with variants of smaller effect will be more difficult but there is no sharp demarcation between large and small genetic effects, so that many new and important insights will emerge using existing and new technologies.

Author(s): 
Wright, A. F.
Publication Title: 
Molecular Cell

Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2.

Author(s): 
Han, Xiao
Gui, Bin
Xiong, Cong
Zhao, Linnan
Liang, Jing
Sun, Luyang
Yang, Xiaohan
Yu, Wenhua
Si, Wenzhe
Yan, Ruorong
Yi, Xia
Zhang, Di
Li, Wanjin
Li, Lifang
Yang, Jianguo
Wang, Yan
Sun, Yi Eve
Zhang, Dai
Meng, Anming
Shang, Yongfeng
Publication Title: 
Cell Death & Disease

Withania somnifera or Ashwagandha is a medicinal herb of Ayurveda. Though the extract and purified molecules, withanolides, from this plant have been shown to have different pharmacological activities, their effect on bone formation has not been studied. Here, we show that one of the withanolide, withaferin A (WFA) acts as a proteasomal inhibitor (PI) and binds to specific catalytic β subunit of the 20S proteasome. It exerts positive effect on osteoblast by increasing osteoblast proliferation and differentiation.

Author(s): 
Khedgikar, V.
Kushwaha, P.
Gautam, J.
Verma, A.
Changkija, B.
Kumar, A.
Sharma, S.
Nagar, G. K.
Singh, D.
Trivedi, P. K.
Sangwan, N. S.
Mishra, P. R.
Trivedi, R.

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