scholarly journals Cellular, ultrastructural and molecular analyses of epidermal cell development in the planarian Schmidtea mediterranea

2017 ◽  
Author(s):  
Li-Chun Cheng ◽  
Kimberly C. Tu ◽  
Chris W. Seidel ◽  
Sofia M.C. Robb ◽  
Fengli Guo ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Transcriptional Regulators ◽  
Precursor Cell ◽  
Schmidtea Mediterranea ◽  
Molecular Analyses ◽  
Lineage Differentiation ◽  
Animal Survival ◽  
Embryonic Origin ◽  
Epidermal Homeostasis ◽  
Invertebrate Organism

AbstractThe epidermis is essential for animal survival, providing both a protective barrier and cellular sensor to external environments. The generally conserved embryonic origin of the epidermis, but the broad morphological and functional diversity of this organ across animals is puzzling. We define the transcriptional regulators underlying epidermal lineage differentiation in the planarian Schmidtea mediterranea, an invertebrate organism that, unlike fruitflies and nematodes, continuously replaces its epidermal cells. We find that Smed-p53, Sox and Pax transcription factors are essential regulators of epidermal homeostasis, and act cooperatively to regulate genes associated with early epidermal precursor cell differentiation, including a tandemly arrayed novel gene family (prog) of secreted proteins. Additionally, we report on the discovery of distinct and previously undescribed secreted organelles whose production is dependent on the transcriptional activity of soxP-3, and which we term Hyman vesicles.

scholarly journals How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance

2021 ◽  
Vol 22 (11) ◽  
pp. 5761
Author(s):  
Anja Wessely ◽  
Theresa Steeb ◽  
Carola Berking ◽  
Markus Vincent Heppt
Keyword(s):  
Drug Resistance ◽  
Neural Crest ◽  
Physiological Function ◽  
Acquired Resistance ◽  
Treatment Resistance ◽  
Transcriptional Regulators ◽  
Disease Stage ◽  
Cellular Plasticity ◽  
Embryonic Origin ◽  
Promote Disease Progression

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.

scholarly journals Homeodomain-Interacting Protein Kinase 1 Modulates Daxx Localization, Phosphorylation, and Transcriptional Activity

2003 ◽  
Vol 23 (3) ◽  
pp. 950-960 ◽  
Author(s):  
Jeffrey A. Ecsedy ◽  
Jennifer S. Michaelson ◽  
Philip Leder
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Transcriptional Activity ◽  
Transcriptional Repressor ◽  
Transcriptional Regulators ◽  
Kinase Domain ◽  
Promyelocytic Leukemia ◽  
Interacting Protein ◽  
Promyelocytic Leukemia Protein

ABSTRACT We describe an interaction between homeodomain-interacting protein kinase 1 (HIPK1) and Daxx, two transcriptional regulators important in transducing growth-regulatory signals. We demonstrate that HIPK1 is ubiquitously expressed in mice and humans and localizes predominantly to the nucleus. Daxx normally resides within the nucleus in promyelocytic leukemia protein (PML) oncogenic domains (PODs), where it physically interacts with PML. Under certain circumstances, Daxx is relocalized from PODs to chromatin, where it then acts as a transcriptional repressor through an association with histone deacetylase (HDAC1). We propose two novel mechanisms for regulating the activity of Daxx, both mediated by HIPK1. First, HIPK1 physically interacts with Daxx in cells and consequently relocalizes Daxx from PODs. Daxx relocalization disrupts its interaction with PML and augments its interaction with HDAC1, likely influencing Daxx activity. Although the relocalization of Daxx from PODs is phosphorylation independent, an active HIPK1 kinase domain is required, suggesting that HIPK1 autophosphorylation is important in this interaction. Second, HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. Mutation of Daxx Ser 669 to Ala results in increased repression in three of four transcriptional reporters, suggesting that phosphorylation by HIPK1 diminishes Daxx transcriptional repression of specific promoters. Taken together, our results indicate that HIPK1 and Daxx collaborate in regulating transcription.

scholarly journals HELZ2 Promotes K63-Linked Polyubiquitination of c-Myc to Induce Retinoblastoma Tumorigenesis

2021 ◽  
Author(s):  
Hanjun Dai ◽  
wen ZENG ◽  
WEIJUAN ZENG ◽  
MING YAN ◽  
ping jiang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Zinc Finger ◽  
Ubiquitin Ligase ◽  
Critical Role ◽  
E3 Ubiquitin Ligase ◽  
Transcriptional Regulators ◽  
Zinc Finger Domain ◽  
Retinoblastoma Cell ◽  
Animal Survival

Abstract Retinoblastoma is a rare ocular tumor in children that originates in the retina. Several core transcriptional regulators maintain the expansion of retinoblastoma tumors, including c-Myc. Here, we demonstrated that Helicase with zinc finger domain 2 (HELZ2) promoted retinoblastoma tumorigenesis by targeting c-Myc. HELZ2-deficient inhibited retinoblastoma cell proliferation, whereas overexpression of HELZ2 promoted retinoblastoma cell proliferation. In addition, high levels of HELZ2 promoted xenograft retinoblastoma tumorigenesis and inhibited animal survival. Mechanistically, HELZ2 interacted with c-Myc and promoted its K63-linked polyubiquitination. We indicated that HELZ2 promoted the interaction between E3 ubiquitin ligase HUWE1 and c-Myc, and HELZ2-mediated K63-linked polyubiquitination and activation of c-Myc were dependent on HUWE1. Taken together, HELZ2 plays a critical role in the regulation of retinoblastoma tumorigenesis by enhancing the activity of c-Myc.

scholarly journals Epilepsy kinase CDKL5 is a DNA damage sensor which controls transcriptional activity at DNA breaks

2020 ◽  
Author(s):  
Taran Khanam ◽  
Ivan Muñoz ◽  
Florian Weiland ◽  
Thomas Carroll ◽  
Barbara N Borsos ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcriptional Control ◽  
Transcriptional Activity ◽  
Transcriptional Regulators ◽  
Human Diseases ◽  
Childhood Epilepsy ◽  
Dna Breaks ◽  
Kinase Gene ◽  
Damage Sensing ◽  
Active Transcription

Mutation of theCDKL5kinase gene leads to the seizure-prone neurodevelopmental condition CDD (CDKL5 deficiency disorder) and is the most common genetic cause of childhood epilepsy. However, the phospho-targets and roles of CDKL5 are poorly understood, especially in the nucleus. We reveal CDKL5 as a sensor of DNA damage in actively transcribed regions of the nucleus, which phosphorylates transcriptional regulators such as Elongin A (ELOA) on a specific consensus motif. Recruitment of CDKL5 and ELOA to DNA damage sites, and subsequent ELOA phosphorylation, requires both active transcription and synthesis of poly–ADP ribose to which CDKL5 can bind. Critically, CDKL5 is essential for transcriptional control at DNA breaks. Therefore, CDKL5 is a DNA damage-sensing regulator of transcription, with implications for CDKL5-related human diseases.One sentence summaryCDKL5 is a DNA damage-sensing kinase that modulates transcriptional activity near DNA breaks.

scholarly journals Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3947
Author(s):  
Gaurav Chauhan ◽  
Hannelore V. Heemers
Keyword(s):  
Prostate Cancer ◽  
Transcriptional Activity ◽  
Transcriptional Regulators ◽  
Dependent Manner ◽  
Improve Treatment ◽  
Castration Resistant ◽  
Treatment Plans ◽  
Somatic Alterations ◽  
Recognition Motifs ◽  
Transcriptional Output

Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.

scholarly journals Multipotent skin-derived precursors: adult neural crest-related precursors with therapeutic potential

2007 ◽  
Vol 363 (1489) ◽  
pp. 185-198 ◽  
Author(s):  
Karl J.L Fernandes ◽  
Jean G Toma ◽  
Freda D Miller
Keyword(s):  
Neural Crest ◽  
Therapeutic Potential ◽  
Precursor Cell ◽  
Cell Type ◽  
Differentiation Potential ◽  
Therapeutic Implications ◽  
Lineage Differentiation ◽  
Mammalian Skin ◽  
Surprising Finding

We previously made the surprising finding that cultures of multipotent precursors can be grown from the dermis of neonatal and adult mammalian skin. These skin-derived precursors (SKPs) display multi-lineage differentiation potential, producing both neural and mesodermal progeny in vitro , and are an apparently novel precursor cell type that is distinct from other known precursors within the skin. In this review, we begin by placing these findings within the context of the rapidly evolving stem cell field. We then describe our recent efforts focused on understanding the developmental biology of SKPs, discussing the idea that SKPs are neural crest-related precursors that (i) migrate into the skin during embryogenesis, (ii) persist within a specific dermal niche, and (iii) play a key role in the normal physiology, and potentially pathology, of the skin. We conclude by highlighting some of the therapeutic implications and unresolved questions raised by these studies.

scholarly journals Cellular, ultrastructural and molecular analyses of epidermal cell development in the planarian Schmidtea mediterranea

2018 ◽  
Vol 433 (2) ◽  
pp. 357-373 ◽  
Author(s):  
Li-Chun Cheng ◽  
Kimberly C. Tu ◽  
Chris W. Seidel ◽  
Sofia M.C. Robb ◽  
Fengli Guo ◽  
...  
Keyword(s):  
Epidermal Cell ◽  
Cell Development ◽  
Schmidtea Mediterranea ◽  
Molecular Analyses

scholarly journals Dicer is selectively important for the earliest stages of erythroid development

Blood ◽  
2012 ◽  
Vol 120 (12) ◽  
pp. 2412-2416 ◽  
Author(s):  
Natalija Buza-Vidas ◽  
Valeriu B. Cismasiu ◽  
Susan Moore ◽  
Adam J. Mead ◽  
Petter S. Woll ◽  
...  
Keyword(s):  
Terminal Differentiation ◽  
Transcriptional Regulators ◽  
Erythroid Progenitors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Lineage Differentiation ◽  
Erythroid Development ◽  
Multilineage Potential ◽  
Proper Balance ◽  
Megakaryocyte Progenitors

Abstract MicroRNAs (miRs) are involved in many aspects of normal and malignant hematopoiesis, including hematopoietic stem cell (HSC) self-renewal, proliferation, and terminal differentiation. However, a role for miRs in the generation of the earliest stages of lineage committed progenitors from HSCs has not been identified. Using Dicer inactivation, we show that the miR complex is not only essential for HSC maintenance but is specifically required for their erythroid programming and subsequent generation of committed erythroid progenitors. In bipotent pre-MegEs, loss of Dicer up-regulated transcription factors preferentially expressed in megakaryocyte progenitors (Gata2 and Zfpm1) and decreased expression of the erythroid-specific Klf1 transcription factor. These results show a specific requirement for Dicer in acquisition of erythroid lineage programming and potential in HSCs and their subsequent erythroid lineage differentiation, and in particular indicate a role for the miR complex in achieving proper balance of lineage-specific transcriptional regulators necessary for HSC multilineage potential to be maintained.

Modulation of transcriptional activity of the DEAD-box family of RNA helicases, p68 (Ddx5) and DP103 (Ddx20), by SUMO modification

2007 ◽  
Vol 35 (6) ◽  
pp. 1427-1429 ◽  
Author(s):  
F.V. Fuller-Pace ◽  
A.-M.F. Jacobs ◽  
S.M. Nicol
Keyword(s):  
Transcriptional Repression ◽  
Transcriptional Activity ◽  
Transcriptional Regulators ◽  
Rna Helicases ◽  
Post Translational Modifications ◽  
Sumo Modification ◽  
Cellular Processes ◽  
Dead Box ◽  
The Dead

SUMO (small ubiquitin-related modifier) modification is known to have diverse effects on the activity of transcriptional regulators, often through alterations in their localization or interactions with other factors, and in most of the cases is associated with transcriptional repression. The DEAD-box family of RNA helicases includes a large number of proteins that are involved in various cellular processes. Several members are now known to be multifunctional and their activities are thought to be governed by interactions with other partners, which may be regulated by post-translational modifications. In the present paper, we shall briefly review recent evidence indicating that SUMO modification is important in modulating the activity of two DEAD-box proteins, p68 (Ddx5) and DP103 (Ddx20), which are known to be important transcriptional regulators.

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