A5060096259- Cancer-related Molecular Pathways
- Epigenetics and DNA Methylation
- Signaling Pathways in Disease
- Advanced Breast Cancer Therapies
- Pancreatic and Hepatic Oncology Research
- Cancer Mechanisms and Therapy
- Galectins and Cancer Biology
- Histone Deacetylase Inhibitors Research
- Cancer Research and Treatments
- Wound Healing and Treatments
- MicroRNA in disease regulation
- Telomeres, Telomerase, and Senescence
- Peptidase Inhibition and Analysis
- Cancer-related gene regulation
- RNA modifications and cancer
- Circadian rhythm and melatonin
- Fibroblast Growth Factor Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Virus-based gene therapy research
- Cancer Cells and Metastasis
- Planarian Biology and Electrostimulation
- Amino Acid Enzymes and Metabolism
- Genetic factors in colorectal cancer
- Ion channel regulation and function
- Genetics and Neurodevelopmental Disorders
Brigham and Women's Hospital
2002-2024
Harvard University
2013-2024
University of North Carolina at Chapel Hill
2004-2023
UNC Lineberger Comprehensive Cancer Center
2006-2023
University of Colorado Anschutz Medical Campus
2019
Massachusetts General Hospital
2008-2013
Pediatrics and Genetics
2004-2007
Howard Hughes Medical Institute
1996
University of Utah
1996
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence aging in vivo, we examined expression rodent models aging. We show that Arf markedly increases almost all tissues with advancing age, while there is little or no change other related cell cycle inhibitors. increase restricted to well-defined compartments within each organ studied occurs both epithelial stromal cells diverse...
With increasing frequency during serial passage in culture, primary human keratinocytes express p16(INK4A) (p16) and undergo senescence arrest. Keratinocytes engineered to hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid greatly reduce p16 expression. We have confirmed that p16-related growth whether the fibroblast feeder cell system specialized K-sfm medium formulation, this mechanism can act as a barrier...
Background Many members of families with inherited long-QT (LQT) syndrome have mutations in HERG , a gene encoding cardiac potassium channel that is modulated by extracellular potassium. We hypothesized an increase serum would normalize repolarization these patients. Methods and Results studied seven subjects chromosome 7–linked LQT five normal control subjects. Repolarization was measured ECG body surface potential mapping during sinus rhythm, exercise, atrial pacing, before after increase....
Total body irradiation (TBI) can induce lethal myelosuppression, due to the sensitivity of proliferating hematopoietic stem/progenitor cells (HSPCs) ionizing radiation (IR). No effective therapy exists mitigate hematologic toxicities TBI. Here, using selective and structurally distinct small molecule inhibitors cyclin-dependent kinase 4 (CDK4) CDK6, we have demonstrated that cellular quiescence increases radioresistance human cell lines in vitro mice vivo. Cell dependent on CDK4/6 were...
Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common lethal cancer, relatively little progress been made in improving outcomes for SCC due to poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression p53-related factor p63. We developed an...
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T immunity. Here, we identify PD-1 as growth-promoting receptor intrinsic to cells. In human lines clinical tumors, RT-PCR–based sequencing, immunoblotting, flow cytometry, immunofluorescence analyses demonstrated gene protein expression MCC–PD-1 ligation enhanced, its inhibition or silencing...
Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cell-intrinsic functional regulation not well understood. Here, we demonstrate induction of in melanoma cells via type I interferon (IFNAR) signaling reversal ICB efficacy through IFNAR pathway inhibition. Treatment with...
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence aging in vivo, we examined expression rodent models aging. We show that Arf markedly increases almost all tissues with advancing age, while there is little or no change other related cell cycle inhibitors. increase restricted to well-defined compartments within each organ studied occurs both epithelial stromal cells diverse...
Squamous cell carcinoma (SCC) is a treatment-refractory subtype of human cancer arising from stratified epithelium the skin, lung, esophagus, oropharynx, and other tissues. A unifying feature SCC high-level expression p53-related protein p63 (TP63) in 80% cases. The major isoform expressed ΔNp63α, an N-terminally truncated form which functions as key survival factor by mechanisms that are unclear. In this study, we show ΔNp63α associates with histone deacetylase 1 (HDAC1) HDAC2 to active...
The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated many human cancers. Therefore, challenge cancer therapy the identification pathways that control cell survival and absence functional p53. p53-related transcription factors p63 p73 exhibit distinct functions—p73 mediates while promotes proliferation survival—and are both overexpressed squamous carcinomas (SCCs). However, how interact govern balance between prosurvival proapoptotic...
Cell cycle progression from G(1) to S phase depends on phosphorylation of pRb by complexes containing a cyclin (D type or E type) and cyclin-dependent kinase (e.g., cdk2, cdk4, cdk6). Ink4 proteins function oppose the action cdk4/6-cyclin D inhibiting cdk4/6. We employed genetic pharmacologic approaches study interplay among cdk4/6 activity in vivo. Mouse embryo fibroblasts (MEF) lacking p16(Ink4a) p18(Ink4c) showed similar growth kinetics as wild-type MEFs despite increased cdk4 activity....
ΔNp63α is a member of the p53 family transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because and bind virtually identical DNA sequence motifs, it has been proposed dominant-negative inhibitor to promote proliferation block apoptosis. However, most SCCs concurrently overexpress inactivate p53, suggesting autonomous action these oncogenic events. Here we report discovery novel mechanism transcriptional repression by reconciles observations. We found...
T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade T-cell-Tim-3 enhances antitumor immunity. Here, we identify additional role for as a growth-suppressive intrinsic to melanoma Inhibition cell-Tim-3 promoted tumor growth both immunocompetent immunocompromised mice, while...
FOXO is thought to function as a repressor of growth that is, in turn, inhibited by insulin signaling. However, inactivating mutations Drosophila melanogaster result viable flies normal size, which raises question over the involvement regulation. Previously, growth-suppressive role for under conditions increased target rapamycin (TOR) pathway activity was described. Here, we further characterize this phenomenon. We show tuberous sclerosis complex 1 cause levels, resulting elevated expression...
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide incidence rates are continuing to rise globally. HNSCC patient prognosis closely related occurrence of tumor metastases, collagen within microenvironment (TME) plays a key role in this process. Lysyl hydroxylase 2 (LH2), encoded by Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase (PLOD2) gene, catalyzes hydroxylation telopeptidyl lysine (Lys) residues fibrillar collagens which then undergo subsequent...