The tumor suppressor p53 is a transcription factor that regulates the expression of a range of target genes in response to cellular stress. Adding to the complexity of understanding its cellular function is that in addition to the full-length protein, several p53 isoforms are produced in humans, harboring diverse expression patterns and functionalities. One isoform, Δ40p53, which lacks the first transactivation domain including the binding region for the negative regulator MDM2, was shown to be a product of alternative translation initiation. Here we report the discovery of an alternative cellular mechanism for Δ40p53 formation. We show that the 20S proteasome specifically cleaves the full-length protein (FLp53) to generate the Δ40p53 isoform. Moreover, we demonstrate that a dimer of FLp53 interacts with a Δ40p53 dimer, creating a functional hetero-tetramer. Consequently, the co-expression of both isoforms attenuates the transcriptional activity of FLp53 in a dominant negative manner. Finally, we demonstrate that following oxidative stress, at the time when the 20S proteasome becomes the major degradation machinery and FLp53 is activated, the formation of Δ40p53 is enhanced, creating a negative feedback loop that balances FLp53 activation. Overall, our results suggest that Δ40p53 can be generated by a 20S proteasome-mediated post-translational mechanism so as to control p53 function. More generally, the discovery of a specific cleavage function for the 20S proteasome may represent a more general cellular regulatory mechanism to produce proteins with distinct functional properties.
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http://dx.doi.org/10.1038/cdd.2017.139 | DOI Listing |
Mol Biol Rep
December 2024
Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamilnadu, 600113, India.
Introduction: The changes in histone modifications are linked to the progression of benign and normal tissue to malignancy. Thus, numerous findings suggest that targeting epigenetic factors might be a focus for anti-cancer treatment. In this study, we tested the hypothesis that telomerase activator might be a potential epigenetic regulator in combatting skin cancer cell proliferation.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2024
College of Plant Protection, China Agricultural University, Beijing 100193, China.
Light is a major determinant of plant growth and survival. NONEXPRESSER OF PATHOGENESIS-RELATED GENES 1 (NPR1) acts as a receptor for salicylic acid (SA) and serves as the key regulator of SA-mediated immune responses. However, the mechanisms by which plants integrate light and SA signals in response to environmental changes, as well as the role of NPR1 in regulating plant photomorphogenesis, remain poorly understood.
View Article and Find Full Text PDFCell Death Dis
December 2024
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Bladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Despite recent approvals of immune checkpoint inhibitors and targeted therapy for muscle invasive or recurrent BC, options remain limited for patients with non-muscle invasive BC (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) and chemotherapy. NMIBC is more frequently classified as a luminal subtype, in which increased PPARγ activity is a key feature in promoting tumor growth and evasion of immunosurveillance.
View Article and Find Full Text PDFSubcell Biochem
December 2024
Department of Biotechnology, Bennett University, Greater Noida, Uttar Pradesh, India.
Ageing is an inevitable phenomenon that remains under control of a plethora of signalling pathways and regulatory mechanisms. Slowing of cellular homeostasis and repair pathways, declining genomic and proteomic integrity, and deficient stress regulatory machinery may cause accumulating damage triggering initiation of pathways leading to ageing-associated changes. Multiple genetic studies in small laboratory organisms focused on the manipulation of proteasomal activities have shown promising results in delaying the age-related decline and improving the lifespan.
View Article and Find Full Text PDFJ Gen Virol
December 2024
Jiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, PR China.
The Bombyx mori nucleopolyhedrovirus (BmNPV) is a DNA virus that affects the silkworm, , causing substantial economic losses in sericulture. This study investigates the mechanisms underlying budded virus egress, focusing on the roles of the ubiquitin-proteasome pathway (UPP) machinery. BmNPV produces two virion types: budded virions (BVs) and occlusion-derived virions (ODVs), which differ in their envelope origins and functions.
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