Elsevier

Blood Cells, Molecules, and Diseases

Volume 31, Issue 2, September–October 2003, Pages 213-228
Blood Cells, Molecules, and Diseases

Regular article
Myeloid differentiation (MyD) primary response genes in hematopoiesis

https://doi.org/10.1016/S1079-9796(03)00160-8Get rights and content

Abstract

Myeloid differentiation (MyD) primary response and growth arrest DNA-damage (Gadd) genes comprise a set of overlapping genes, including known (IRF-1, EGR-1, Jun) and novel (MyD88, Gadd45a MyD118/Gadd45b, GADD45g, MyD116/Gadd34) genes, that have been cloned by virtue of being coordinately induced upon the onset of terminal myeloid differentiation. This review delineates the role MyD genes were found to play in blood cell development, where they function as positive regulators of terminal differentiation, lineage specific blood cell development, and control of blood cell homeostasis, including growth inhibition and apoptosis.

Section snippets

Introduction: terminal differentiation, negative growth control, and MyD/Gadd genes

Animal cells respond to differentiation signals which turn on or off the appropriate genes, resulting in the conversion of proliferating undifferentiated cells into nonproliferating, highly specialized differentiated cells. Two interrelated cellular processes are invoked simultaneously upon induction of differentiation, the regulated progression of cells through successive stages of cell differentiation and growth inhibition which ultimately leads to growth arrest. In tissues with rapid cell

Interferon regulatory factor 1 (IRF-1/MyD32) in hematopoiesis, immunity, and negative growth control

Interferon regulatory factor-1 (IRF-1), a transcriptional activator of the interferon-b (IFNb) gene [8], [9], [10], has been isolated in this laboratory as MyD32, a MyD gene that was observed to be highly expressed in normal myeloblast enriched bone-marrow cells [2]. IRF-1/MyD32 was observed to be rapidly induced in the absence of de novo protein synthesis in M1 myeloblastic leukemia cells induced for terminal differentiation by IL6 or leukemia inhibitory factor (LIF). IRF-1 induction in M1

Jun/Fos transcription factors (MyD21, MyD42, MyD63) in hematopoietic differentiation and as modulators of stress-induced apoptosis

MyD21, MyD42, and MyD63 were identified as MyD genes that encode for leucine zipper proteins that are rapidly and stably induced during differentiation of M1 myeloblastic leukemia cells, and myeloblast enriched bone-marrow cells. Shortly after their isolation cloning of c-jun, JunB, and JunD have been reported [28], [29], [30], [31], [32], and it became evident that MyD21, MyD42, and MyD63. encode for junB, c-Jun, and JunD, respectively [1], [3], [33]. The fact that jun mRNAs are stabley

MyD19/HLM38: Egr-1-modulates hematopoietic lineage specific differentiation, and host stress responses

MyD19 and HLM38 were identified as myeloid differentiation primary response cDNAs, encoding for similar zinc finger proteins that are rapidly induced upon activation of terminal macrophage differentiation in M1 myeloblastic leukemia cells and HL60 promyelocyic leukemia cells, respectively. Shortly after, it became evident that MyD19 and HLM38 encode for the mouse and human homologous of the newly discovered zinc finger transcription factor EGR-1 [43], [44], [45]. That Egr-1 was specifically

MyD88—a signal transducer in IL-1 and Toll receptor signaling: role in innate immunity, inflammation, and apoptosis

MyD88 was originally characterized as a novel MyD gene in M1 myeloblastic leukemia cells induced for terminal macrophage differentiation by IL-6 [7]. High levels of MyD88 are observed in myeloid enriched bone marrow cells, suggesting a role for this gene in myeloid cell function/development. Interestingly, MyD88 immediate early induction, unlike other MyD genes, was found to be largely regulated at the level of mRNA stability [53]. The role of MyD88 in terminal myeloid differentiation is still

MyD116—Viral homologs and role in apoptosis

MyD116 is the second novel MyD gene that was isolated in our laboratory [6]. Like other MyD genes, it is rapidly induced by IL-6 in M1, and expressed in bone marrow cells. Following its isolation, it became evident that MyD116 is the murine homologue of Gadd34 that was isolated by virtue of its being activated in hamster cells by growth arrest and DNA damage stimuli, including alkylating agents and irradiation [136], [137], [138]. An interesting feature of the MyD116/GADD34 proteins are the

MyD118(GADD45b), Gadd45a, and CR6(GADD45g)—a family of growth suppressive and apoptotic proteins which interact's with cell cycle proteins

MyD118 was the third novel gene isolated in our laboratory [5]. Shortly after its isolation, it became evident that MyD118 is related to the Gadd45 gene. The proteins encoded by these genes are 57% identical, indicating that MyD118 and Gadd45 represent two separate but closely related genes [138]. Recently, the full-length sequences of murine and human CR6 cDNAs, respectively, have been determined [160], [161], Recently, comparative analysis of the genetic structure and chromosomal mapping of

The MyD/GADD network of interactions

What has been described above depicts an intricate network of interactions among MyD/GADD genes and gene products which appears to function in blood cell differentiation, cell homeostasis, and host stress responses (Fig. 3). It is evident that MyD/Gadd, each in its own way, play, a role in blood cell development, where they function as positive regulators of the terminal differentiation program (jun/Fos), in lineage specific cell development (EGR-1), and in the control of blood cell

Acknowledgements

This research was supported by National Institute's of Health Grants 1RO1 CA89718 and 1R01 HL 70530 (to D.A.L.). This paper is based on a presentation from the Fifth International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia held at Annapolis, May 4–7, 2003, sponsored by the Leukemia and Lymphoma Society.

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