A small-molecule inhibitor of TopBP1 exerts anti-MYC activity and synergy with PARP inhibitors.

We have previously identified TopBP1 (topoisomerase IIβ-binding protein 1) as a promising target for cancer therapy, given its role in the convergence of Rb, PI(3)K/Akt, and p53 pathways. Based on this, we conducted a large-scale molecular docking screening to identify a small-molecule inhibitor that specifically targets the BRCT7/8 domains of TopBP1, which we have named 5D4. Our studies show that 5D4 inhibits TopBP1 interactions with E2F1, mutant p53, and Cancerous Inhibitor of Protein Phosphatase 2A.

DNA2 Nuclease Inhibition Confers Synthetic Lethality in Cancers with Mutant p53 and Synergizes with PARP Inhibitors.

Unlabelled: The tumor suppressor p53 promotes tumor-suppressive activities including cell-cycle inhibition, apoptosis, senescence, autophagy, and DNA repair. However, somatic mutations in the TP53 gene are one of the most common alterations in human cancers. We previously showed that mutant p53 (mutp53) can bind TopBP1, an ATR activator, to attenuate its ATR-activating function.

A novel prediction model of the risk of pancreatic cancer among diabetes patients using multiple clinical data and machine learning.

Introduction: Pancreatic cancer is associated with poor prognosis. Considering the increased global incidence of diabetes cases and that individuals with diabetes are considered a high-risk subpopulation for pancreatic cancer, it is critical to detect the risk of pancreatic cancer within populations of person living = with diabetes. This study aimed to develop a novel prediction model for pancreatic cancer risk among patients with diabetes, using = a real-world database containing clinical features and employing numerous artificial intelligent approach algorithms.

Associations of Warfarin Use with Risks of Ischemic Cerebrovascular Events and Major Bleeding in Patients with Hyperthyroidism-Related Atrial Fibrillation.

The use of oral anticoagulants for patients with new-onset hyperthyroidism-related atrial fibrillation (AF) is controversial. We aimed to evaluate the clinical benefits of warfarin therapy in this population. This retrospective cohort study used a data-cut of Taiwan Health and Welfare Database between 2000 and 2016.

14-3-3τ drives estrogen receptor loss via ERα36 induction and GATA3 inhibition in breast cancer.

About one-fourth of recurrent estrogen receptor-positive (ER+) breast cancers lose ER expression, leading to endocrine therapy failure. However, the mechanisms underlying ER loss remain to be fully explored. We now show that 14-3-3τ, up-regulated in ∼60% of breast cancer, drives the conversion of ER+ to ER- and epithelial-to-mesenchymal transition (EMT).

Effectiveness and Safety of Immunosuppressants and Biological Therapy for Chronic Spontaneous Urticaria: A Network Meta-Analysis.

Chronic spontaneous urticaria (CSU) is the most common phenotype of chronic urticaria. We compared treatment effects and safety profiles of the medications in patients with CSU. We searched PubMed, MEDLINE, and Web of Science for randomized control trials (RCTs), from 1 January 2000 to 31 July 2021, which evaluated omalizumab and immunosuppressants.

RNF144A deficiency promotes PD-L1 protein stabilization and carcinogen-induced bladder tumorigenesis.

RNF144A is a DNA damage-induced E3 ubiquitin ligase that targets proteins involved in genome instability for degradation, e.g., DNA-PKcs and BMI1.

Central nervous system intravascular lymphoma leading to rapidly progressive dementia.

Intravascular lymphoma is an uncommon subtype of B-cell lymphoma with neoplastic cells limited to the lumen of small blood vessels. We report a case of a 52-year-old man who presented with constitutional symptoms and rapidly progressive dementia. He was found to have diffuse leptomeningeal and faint parenchymal enhancement on magnetic resonance imaging and was subsequently diagnosed with intravascular lymphoma following a brain biopsy.

Overexpression of TopBP1, a canonical ATR/Chk1 activator, paradoxically hinders ATR/Chk1 activation in cancer.

Topoisomerase IIβ-binding protein 1 (TopBP1) is involved in cellular replication among other functions and is known to activate ATR/Chk1 during replicative stress. TopBP1 is also expressed at high levels in many cancers. However, the impact of TopBP1 overexpression on ATR/Chk1 activation and cancer development has not been investigated.

ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer.

Cisplatin is a mainstay of systemic therapy for a variety of cancers, such as lung cancer, head and neck cancer, and ovarian cancer. However, resistance to cisplatin represents one of the most significant barriers for patient outcome improvement. Actin-like 6A (ACTL6A) is a component of several chromatin remodeling complexes, including SWI/SNF, NuA4/TIP60 histone acetylase, and INO80.

E2F1 sumoylation as a protective cellular mechanism in oxidative stress response.

Oxidative stress is a ubiquitous threat to all aerobic organisms and has been implicated in numerous pathological conditions such as cancer. Here we demonstrate a pivotal role for E2F1, a cell cycle regulatory transcription factor, in cell tolerance of oxidative stress. Cells lacking E2F1 are hypersensitive to oxidative stress due to the defects in cell cycle arrest.

Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt.

Cdk2-dependent TopBP1-treslin interaction is critical for DNA replication initiation. However, it remains unclear how this association is terminated after replication initiation is finished. Here, we demonstrate that phosphorylation of TopBP1 by Akt coincides with cyclin A activation during S and G phases and switches the TopBP1-interacting partner from treslin to E2F1, which results in the termination of replication initiation.

CGRRF1, a growth suppressor, regulates EGFR ubiquitination in breast cancer.

Background: CGRRF1 is a growth suppressor and consists of a transmembrane domain and a RING-finger domain. It functions as a RING domain E3 ubiquitin ligase involved in endoplasmic reticulum-associated degradation. The expression of CGRRF1 is decreased in cancer tissues; however, the role of CGRRF1 in breast cancer and the mechanism(s) of its growth suppressor function remain to be elucidated.

RNF144A sustains EGFR signaling to promote EGF-dependent cell proliferation.

RNF144A is a single-pass transmembrane RBR E3 ligase that interacts with and degrades cytoplasmic DNA-PKcs, which is an epidermal growth factor receptor (EGFR)-interacting partner. Interestingly, RNF144A expression is positively correlated with EGFR mRNA and protein levels in several types of cancer. However, the relationship between RNF144A and EGFR is poorly understood.

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin.

Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73.

TRIP6 antagonizes the recruitment of A20 and CYLD to TRAF6 to promote the LPA2 receptor-mediated TRAF6 activation.

The elevated lysophosphatidic acid signaling has been causally linked to cancer-associated inflammation and tumorigenesis through upregulation of nuclear factor-κB signaling. However, how this signaling event is regulated has not yet been fully understood. Here we demonstrate that TRIP6, an LPA2 receptor-interacting adaptor protein, functions as a positive regulator of nuclear factor-κB and JNK signaling through direct binding to and activation of the E3 ligase TRAF6.

Regulation of E2 promoter binding factor 1 (E2F1) transcriptional activity through a deubiquitinating enzyme, UCH37.

E2F1 is tightly controlled by multiple mechanisms, but whether ubiquitination regulates its transcriptional activity remains unknown. Here we identify UCH37 as the first, to our knowledge, deubiquitinating enzyme for E2F1. UCH37 does not deubiquitinate UbK48 chains or affect E2F1 protein stability.

Regulation of RNF144A E3 Ubiquitin Ligase Activity by Self-association through Its Transmembrane Domain.

RNF144A, an E3 ubiquitin ligase for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), can promote DNA damage-induced cell apoptosis. Here we characterize an important regulation of RNF144A through its transmembrane (TM) domain. The TM domain of RNF144A is highly conserved among species.

Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy.

The progression of many solid tumours is driven by deregulation of multiple common pathways, particularly Rb, PI(3)K/Akt and p53. Prior studies identified TopBP1 as a key mediator for the oncogenic gain-of-function activities of mutant p53 (mutp53) in cancer. In Akt-hyperactive cancer, TopBP1 forms oligomers and represses E2F1-dependent apoptosis.

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage.

Several ring between ring fingers (RBR) -domain proteins, such as Parkin and Parc, have been shown to be E3 ligases involved in important biological processes. Here, we identify a poorly characterized RBR protein, Ring Finger protein 144A (RNF144A), as the first, to our knowledge, mammalian E3 ubiquitin ligase for DNA-PKcs. We show that DNA damage induces RNF144A expression in a p53-dependent manner.

14-3-3τ promotes breast cancer invasion and metastasis by inhibiting RhoGDIα.

14-3-3τ is frequently overexpressed in breast cancer; however, whether it contributes to breast cancer progression remains undetermined. Here, we identify a critical role for 14-3-3τ in promoting breast cancer metastasis, in part through binding to and inhibition of RhoGDIα, a negative regulator of Rho GTPases and a metastasis suppressor. 14-3-3τ binds Ser174-phosphorylated RhoGDIα and blocks its association with Rho GTPases, thereby promoting epidermal growth factor (EGF)-induced RhoA, Rac1, and Cdc42 activation.

Akt switches TopBP1 function from checkpoint activation to transcriptional regulation through phosphoserine binding-mediated oligomerization.

Our previous study showed that Akt phosphorylates TopBP1 at the Ser-1159 residue and induces its oligomerization. Oligomerization is required for TopBP1 to bind and repress E2F1 activity. However, the mechanism through which phosphorylation of TopBP1 by Akt leads to its oligomerization remains to be determined.

TRIP6 regulates p27 KIP1 to promote tumorigenesis.

TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27(KIP1) to AKT in the cytosol.