The p53-dependent ubiquitin ligase Pirh2 regulates a number of proteins involved in different cancer-associated processes. Targeting the p53 family proteins, Chk2, p27, Twist1 and others, Pirh2 participates in such cellular processes as proliferation, cell cycle regulation, apoptosis and cellular migration. Thus, it is not surprising that Pirh2 takes part in the initiation and progression of different diseases and pathologies including but not limited to cancer. In this review, we aimed to summarize the available data on Pirh2 regulation, its protein targets and its role in various diseases and pathological processes, thus making the Pirh2 protein a promising therapeutic target.
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http://dx.doi.org/10.3390/cells11091515 | DOI Listing |
Mol Cancer
October 2024
Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Background: Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.
Methods: We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response.
Front Chem
July 2024
School of Physical Sciences, Amrita Vishwa Vidyapeetham, Mysuru Campus, Mysuru, India.
Leukemia is a global health concern that requires alternative treatments due to the limitations of the FDA-approved drugs. Our focus is on p53, a crucial tumor suppressor that regulates cell division. It appears possible to stabilize p53 without causing damage to DNA by investigating dual-acting inhibitors that target both ligases.
View Article and Find Full Text PDFCell Death Dis
May 2024
Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
Pirh2 is an E3 ubiquitin ligase known to regulate the DNA damage responses through ubiquitylation of various participating signaling factors. DNA damage is a key pathological contributor to Alzheimer's disease (AD), therefore, the role of Pirh2 was investigated in streptozotocin and oligomer Aβ induced rodent experimental model of AD. Pirh2 protein abundance increased during AD conditions, and transient silencing of Pirh2 inhibited the disease-specific pathological markers like level of p-Tau, βamyloid, acetylcholinesterase activity, and neuronal death.
View Article and Find Full Text PDFCell Rep
March 2024
Center for Medical Research, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China. Electronic address:
The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC pathway involves nuclear export mediator factor (NEMF)-dependent recruitment of the E3 ligase Listerin to ubiquitinate ribosome-stalled nascent polypeptides on the lysine residue for degradation. However, the quality control of ribosome-stalled nuclear-encoded mitochondrial nascent polypeptides remains elusive, as these peptides can be partially imported into mitochondria through translocons, restricting accessibility to the lysine by Listerin.
View Article and Find Full Text PDFJ Cell Physiol
December 2023
Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, India.
Amyloid-β (Aβ) protein aggregation in the brain is a pathological hallmark of Alzheimer's disease (AD) however, the underlying molecular mechanisms regulating amyloid aggregation are not well understood. Here, we studied the propitious role of E3 ubiquitin ligase Pirh2 in Aβ protein aggregation in view of its regulatory ligase activity in the ubiquitin-proteasome system employing both cellular and sporadic rodent models of AD. Pirh2 protein abundance was significantly increased during Streptozotocin (STZ) induced AD conditions, and transient silencing of Pirh2 significantly inhibited the Aβ aggregation and modified the dendrite morphology along with the substantial decrease in choline level in the differentiated neurons.
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