CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control

Abstract

MyD118 and Gadd45 are two related genes which encode for proteins that play important roles in negative growth control, including both growth suppression and apoptosis. A strategy was employed to clone new members of the MyD118 and Gadd45 family of genes. Based on alignment of the deduced amino acid sequences, one cDNA clone was found to encode for the murine homologue of human CR6, originally cloned as an IL-2 immediate-early response gene. The murine and human CR6 proteins were observed to be 97% identical, indicating that CR6 is an evolutionarily conserved protein. Analysis of CR6 expression during hematopoietic cell development associated with growth arrest and apoptotic cell death, upon exposure of hematopoietic cells to a variety of growth arrest and apoptotic stimuli, and in a variety of murine tissues, has revealed that CR6 expression diers signi®cantly from the expression of the related MyD118 and Gadd45 genes. Nevertheless, CR6, like MyD118 and Gadd45, suppressed colony formation of human lung carcinoma H1299 cells. These data suggest that CR6 plays similar, but not identical, roles to MyD118 and Gadd45 in negative control of cell growth.

Molecular Responses of Human Lung Epithelial Cells to the Toxicity of Copper Oxide Nanoparticles Inferred from Whole Genome Expression Analysis

“…GADD45B and GADD45G are members of the GADD45 family of proteins that are induced by genotoxic stresses and various apoptotic cytokines [11][12][13] and are involved in cell cycle arrest, [14][15][16][17][18][19] DNA repair, [20][21][22] cell survival, [22][23][24][25][26][27] and apoptosis. These functions are mediated by proliferating cell nuclear antigen (PCNA), cell division control 2 (CDC2), cyclin B1 (CCNB1), and cyclin-dependent kinase inhibitor 1A (CDKN1A; also known as p21), which are classified in the GO "cell cycle" category.…”

Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

“…Gadd45a, Gadd45b (also termed MyD118) and Gadd45g (also termed CR6) constitute a family of genes, which encode for small (18 kDa) evolutionarily conserved proteins that are highly homologous to each other, are highly acidic and are localized primarily, but not exclusively, within the cell nucleus Takekawa and Saito, 1998;Zhang et al, 1999). Despite marked similarities, these genes are regulated differently and exhibit functional diversity (Liebermann and Hoffman, 2003).…”

“…Only Gadd45a was found to be a p53 target gene (Kastan et al, 1992;Vairapandi et al, 1996). Gadd45b and gadd45g are induced by inflammatory cytokines such as interleukin (IL)-6, IL-12 and IL-18 (Zhang et al, 1999;Lu et al, 2001;Yang et al, 2001). Additionally, gadd45b was induced by tumor necrosis factor (TNF)-a (De Smaele et al, 2001;Amanullah et al, 2003), transforming growth factor (TGF-b) (Selvakumaran et al, 1994;Takekawa et al, 2002;Yoo et al, 2003) and innate immunity signals arising from lipopolysaccharide stimulation (Lang et al, 2002).…”

“…Overall, Gadd45a, Gadd45b and Gadd45g have been implicated in cell cycle arrest (Beadling et al, 1993;Hollander et al, 1999;Wang et al, 1999;Zhang et al, 1999), DNA repair (Smith et al, 1994;Vairapandi et al, 1996), apoptosis (Harkin et al, 1999;Vairapandi et al, 2000;Azam et al, 2001;Takekawa et al, 2002;Yoo et al, 2003), cell survival (Smith et al, 1996;De Smaele et al, 2001;Zazzeroni et al, 2003;Papa et al, 2004;Gupta et al, 2005), genomic stability (Hollander et al, 1999), inflammatory response and innate immunity (Lu et al, 2001;Yang et al, 2001;Lu et al 2004). Gadd45 proteins have been shown to stimulate the p38-c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways in response to stress situations and thereby sensitize cells for growth arrest, apoptosis or survival (Takekawa and Saito, 1998;Harkin et al, 1999;De Smaele et al, 2001;Lu et al, 2001;Hildesheim et al, 2002;Yoo et al, 2003).…”

“…Gadd45 gene(s) were also found to be primary response gene(s) to IL-6-mediated terminal differentiation of M1 monocytic leukemia cells, as well as to granulocyte colony-stimulating factor (G-CSF)-mediated terminal differentiation of 32Dcl3 cells; furthermore, gadd45 gene(s) were induced by myeloid differentiation-inducing cytokines such as IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) (Zhang et al, 1999) in primary murine bone marrow (BM) cells (Abdollahi et al, 1991;Zhang et al, 1999). Induction of gadd45 genes at the onset of myeloid differentiation in response to various cytokines indicates that Gadd45 protein(s) may play a role in hematopoiesis (Abdollahi et al, 1991;Zhang et al, 1999).…”