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Cell Cycle Regulators and Lineage-Specific Therapeutic Targets for Cushing Disease.

ABSTRACT: Cell cycle proteins are critical to pituitary development, but their contribution to lineage-specific tumorigenesis has not been well-elucidated. Emerging evidence from in vitro human tumor analysis and transgenic mouse models indicates that G1/S-related cell cycle proteins, particularly cyclin E, p27, Rb, and E2F1, drive molecular mechanisms that underlie corticotroph-specific differentiation and development of Cushing disease. The aim of this review is to summarize the literature and discuss the complex role of cell cycle regulation in Cushing disease, with a focus on identifying potential targets for therapeutic intervention in patients with these tumors.

SUBMITTER: Araki T

PROVIDER: S-EPMC6096271 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cell Cycle Regulators and Lineage-Specific Therapeutic Targets for Cushing Disease.

Araki Takako T Liu Ning-Ai NA

Frontiers in endocrinology 20180810

Cell cycle proteins are critical to pituitary development, but their contribution to lineage-specific tumorigenesis has not been well-elucidated. Emerging evidence from <i>in vitro</i> human tumor analysis and transgenic mouse models indicates that G1/S-related cell cycle proteins, particularly cyclin E, p27, Rb, and E2F1, drive molecular mechanisms that underlie corticotroph-specific differentiation and development of Cushing disease. The aim of this review is to summarize the literature and di ...[more]

PMID: 30147673

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Project description:Allogenic hematopoietic stem cell transplantation (allo-HSCT) represents a potent and potentially curative treatment for many hematopoietic malignancies and hematologic disorders in adults and children. The donor-derived immunity, elicited by the stem cell transplant, can prevent disease relapse but is also responsible for the induction of graft-versus-host disease (GVHD). The pathophysiology of acute GVHD is not completely understood yet. In general, acute GVHD is driven by the inflammatory and cytotoxic effect of alloreactive donor T cells. Since several experimental approaches indicate that CD4 T cells play an important role in initiation and progression of acute GVHD, the contribution of the different CD4 T helper (Th) cell subtypes in the pathomechanism and regulation of the disease is a central point of current research. Th lineages derive from naïve CD4 T cell progenitors and lineage commitment is initiated by the surrounding cytokine milieu and subsequent changes in the transcription factor (TF) profile. Each T cell subtype has its own effector characteristics, immunologic function, and lineage specific cytokine profile, leading to the association with different immune responses and diseases. Acute GVHD is thought to be mainly driven by the Th1/Th17 axis, whereas Treg cells are attributed to attenuate GVHD effects. As the differentiation of each Th subset highly depends on the specific composition of activating and repressing TFs, these present a potent target to alter the Th cell landscape towards a GVHD-ameliorating direction, e.g. by inhibiting Th1 and Th17 differentiation. The finding, that targeting of Th1 and Th17 differentiation appears more effective for GVHD-prevention than a strategy to inhibit Th1 and Th17 cytokines supports this concept. In this review, we shed light on the current advances of potent TF inhibitors to alter Th cell differentiation and consecutively attenuate GVHD. We will focus especially on preclinical studies and outcomes of TF inhibition in murine GVHD models. Finally, we will point out the possible impact of a Th cell subset-specific immune modulation in context of GVHD.

Dataset Information

Cell Cycle Regulators and Lineage-Specific Therapeutic Targets for Cushing Disease.

Publications

Cell Cycle Regulators and Lineage-Specific Therapeutic Targets for Cushing Disease.

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