KANSL2 and MBNL3 are regulators of pancreatic ductal adenocarcinoma invasion.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. One major reason for this is that PDAC quickly metastasizes to other organs, thereby making its treatment difficult. The molecular machinery driving PDAC metastasis is still poorly understood.

Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.

The human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in their structure and substrate preference. Whereas CYP3A4 is predominantly expressed in the liver, CYP3A5 is upregulated in cancer, contributing to drug resistance. Selective inhibitors of CYP3A5 are, therefore, critical to validating it as a therapeutic target.

A high-throughput screening identifies histone deacetylase inhibitors as therapeutic agents against medulloblastoma.

Background: Medulloblastoma is the most frequently occurring malignant brain tumor in children. Current treatment strategies for medulloblastoma include aggressive surgery, cranio-spinal irradiation and adjuvant chemotherapy. Because current treatments can cause severe long-term side effects and are not curative, successful treatment remains a challenge.

Genome-wide CRISPR screen reveals PSMA6 to be an essential gene in pancreatic cancer cells.

Background: Despite its relatively low incidence, pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths because of the aggressive growth/metastasis of the tumor, the lack of early symptoms, and the poor treatment options. Basic research to identify potential therapeutic targets for PDAC is greatly needed.

Methods: We used a negative-selection genome-wide CRISPR screen to identify essential genes in the PANC-1 human pancreatic carcinoma cell line.

RNA interference screen identifies NAA10 as a regulator of PXR transcription.

The pregnane X receptor (PXR) is a principal xenobiotic receptor crucial in the detection, detoxification, and clearance of toxic substances from the body. PXR plays a vital role in the metabolism and disposition of drugs, and elevated PXR levels contribute to cancer drug resistance. Therefore, to modulate PXR activity and mitigate drug resistance, it is imperative to fully understand its regulation.

PXR: More Than Just a Master Xenobiotic Receptor.

Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic-sensing function.

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase.

Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. There has been mounting evidence of crosstalk between the drug metabolism pathway and the energy metabolism pathway, but little is known about this cross-regulation. To further delineate the energy metabolism and drug metabolism crosstalk in this study, we exposed HepG2 cells to varying glucose concentrations.

Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk.

Introduction: Protein-protein interaction and signaling crosstalk contribute to the regulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and broaden their cellular function.

Area Covered: This review covers key historic discoveries and recent advances in our understanding of the broad function of PXR and CAR and their regulation by protein-protein interaction and signaling crosstalk.

Expert Opinion: PXR and CAR were first discovered as xenobiotic receptors; however, it is clear that PXR and CAR perform a much broader range of cellular functions through protein-protein interaction and signaling crosstalk, which typically mutually affect the function of all the partners involved.

PAK1 translocates into nucleus in response to prolactin but not to estrogen.

Tyrosyl phosphorylation of the p21-activated serine-threonine kinase 1 (PAK1) has an essential role in regulating PAK1 functions in breast cancer cells. We previously demonstrated that PAK1 serves as a common node for estrogen (E2)- and prolactin (PRL)-dependent pathways. We hypothesize herein that intracellular localization of PAK1 is affected by PRL and E2 treatments differently.

Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1.

Serine/threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer. However, the integration of PAK1 into the estrogen response is not fully understood. In this study, we investigated the mechanisms underlying the hormone-induced activation of estrogen receptor (ERα, ESR1).

A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation.

Differentiation-inducing factors 1-3 (DIFs 1-3), chlorinated alkylphenones identified in the cellular slime mold are considered anti-tumor agents because they inhibit proliferation of a variety of mammalian tumor cells . Although the anti-proliferative effects of DIF-1 and DIF-3 are well-documented, the precise molecular mechanisms underlying the actions of DIFs have not been fully elucidated. In this study, we examined the effects of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation.

Phosphorylation of tyrosine 285 of PAK1 facilitates βPIX/GIT1 binding and adhesion turnover.

The p21-activated serine-threonine kinase (PAK1) regulates cell motility and adhesion. We have previously shown that the prolactin (PRL)-activated tyrosine kinase JAK2 phosphorylates PAK1 in vivo and in vitro and identified tyrosines 153, 201, and 285 in PAK1 as sites of JAK2 tyrosyl phosphorylation. Here, we further investigate the role of the tyrosyl phosphorylated PAK1 (pTyr-PAK1) in regulation of cell adhesion.

PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV.

p21-Activated serine-threonine kinase (PAK1) is implicated in breast cancer. We have shown previously that PAK1 is tyrosyl phosphorylated by prolactin (PRL)-activated Janus tyrosine kinase (JAK2). Although a role for both PRL and PAK1 in breast cancer is widely acknowledged, the mechanism remains poorly understood.

Tyrosyl phosphorylated PAK1 regulates breast cancer cell motility in response to prolactin through filamin A.

The p21-activated serine-threonine kinase (PAK1) is activated by small GTPase-dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation.

Identification of novel mitosis regulators through data mining with human centromere/kinetochore proteins as group queries.

Background: Proteins functioning in the same biological pathway tend to be transcriptionally co-regulated or form protein-protein interactions (PPI). Multiple spatially and temporally regulated events are coordinated during mitosis to achieve faithful chromosome segregation. The molecular players participating in mitosis regulation are still being unravelled experimentally or using in silico methods.

PAK1-Nck regulates cyclin D1 promoter activity in response to prolactin.

Prolactin (PRL) is critical for alveolar proliferation and differentiation in normal mammary development and is also implicated in breast cancer. PRL influences cell proliferation and growth by altering the expression of cyclin D1. Cyclin D1 expression is directly regulated by PRL through the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5-mediated transcriptional activation of the cyclin D1 promoter.