The AMBRA1 E3 ligase adaptor regulates the stability of cyclinD.
The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclinD) couple these inputs to the initiation of DNA replication1. Increased levels of cyclinD promote cell division by activating cyclin-dependent kinases4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclinD-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer2,3. However, the mechanisms that regulate levels of cyclinD are incompletely understood4,5. Here we show that autophagy and beclin1 regulator1 (AMBRA1) is the main regulator of the degradation of cyclinD. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclinD in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclinD as a substrate receptor for the cullin4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclinD, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.
View details for DOI 10.1038/s41586-021-03474-7
View details for PubMedID 33854239
Dynamic shifts in chromatin states differentially mark the proliferative basal cells and terminally differentiated cells of the developing epidermis
Post-translational modifications on nucleosomal histones represent a key epigenetic regulatory mechanism to mediate the complex gene expression, DNA replication, and cell cycle changes that occur in embryonic cells undergoing lineage specification, maturation, and differentiation during development. Here, we investigated the dynamics of 13 key histone marks in epidermal cells at three distinct stages of embryonic skin development and identified significant changes that corresponded with the maturation of the proliferative basal epidermal cells and terminally differentiated cells in the stratified layers. In particular, H3K4me3 and H3K27ac were accumulated and became more prominent in the basal cells at later stages of epidermal development, while H3K27me3 was found to be low in the basal cells but highly enriched in the differentiated suprabasal cell types. Constitutive heterochromatin marked by H4K20me3 was also significantly elevated in differentiated epidermal cells at late gestation stages, which exhibited a concomitant loss of H4K16 acetylation. These differential chromatin profiles were established in the embryonic skin by gestation day 15 and further amplified at E18 and in postnatal skin. Our results reveal the dynamic chromatin states that occur as epidermal progenitor cells commit to the lineage and differentiate into the different cells of the stratified epidermis and provide insight to the underlying epigenetic pathways that support normal epidermal development and homoeostasis.
View details for DOI 10.1080/15592294.2020.1738028
View details for Web of Science ID 000520366100001
View details for PubMedID 32175801
Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells.
Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.
View details for DOI 10.1016/j.ccell.2020.05.003
View details for PubMedID 32531271
Intra- and intertumoral heterogeneity and response to therapy in mouse models of SCLC.
AMER ASSOC CANCER RESEARCH. 2018: 18
View details for Web of Science ID 000432307300009
Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models
TRANSLATIONAL LUNG CANCER RESEARCH
2018; 7 (1): 21–31
Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth. We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents. A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.
View details for PubMedID 29535910
View details for PubMedCentralID PMC5835592