Cytokine response gene 8 (CR8) regulates the cell cycle G1-S phase transition and promotes cellular survival

Abstract

Cellular proliferation and survival are modulated by the expression of speci®c genes. Cytokine response gene 8 (CR8), which was originally cloned as an IL-2-induced gene in human T lymphocytes, encodes a basic helix ± loop ± helix (bHLH) transcription factor. The CR8 gene product is highly conserved among human, mouse and rat, and contains sequence motifs that distinguish it from other bHLH families. The CR8 gene is ubiquitously expressed, and CR8 gene expression is induced by both growth-promoting as well as growth-inhibitory stimuli. As bHLH proteins have been found to regulate both the G1-S phase cell cycle transition, as well as cellular survival, the eects of CR8 on these processes were investigated. Ectopic CR8 expression in asynchronous U2OS cell cultures reduces the percentage of cells in the cell cycle S phase, and also slows the entry of G1-synchronized cells into S phase. The prolonged G1 interval correlates with impaired elevation of cyclin E protein and prolonged p21 protein expression in G1. CR8 expression also protects U2OS cells from serum-withdrawal induced apoptosis. These results indicate that CR8 is an important modulator of both the G1-S phase cell cycle transition, and cellular survival. Oncogene (2001) 20, 1771 ± 1783.

SUMO Modification of Stra13 Is Required for Repression of Cyclin D1 Expression and Cellular Growth Arrest

“…However, the molecular mechanisms through which Stra13 regulates these diverse biological responses are largely unclear. Previous studies have shown that Stra13 overexpression results in growth suppression, cell cycle arrest, and cellular senescence, which are important tumor suppression mechanisms [4], [6], [10], [12], [17]. Consistent with these observations, Stra13 expression is indeed down regulated in some tumors.…”

bHLH-Orange Transcription Factors in Development and Cancer

“…In contrast, loss of Stra13 results in reduced apoptosis of lymphocytes Thin et al 2007), and its overexpression results in increased cell death in 293T cells (Ivanova et al 2004). The down regulation of Stra13 in lung and colon cancer is consistent with many previous studies demonstrating that Stra13 causes growth arrest in a number of cell types (Sun and Taneja, 2000;Beadling et al 2001;Li et al 2002;Zawel et al 2002;Seimiya et al 2004), as well as the fact that it is expressed in most normal tissues that are differentiated Ivanova et al 2005;Sun et al 2007). Moreover, Stra13 promotes differentiation of a number of cell types such as chondrocytes (Shen et al 2002), osteoblasts (Iwata et al 2006), trophoblasts (Hughes et al 2004), and neurons (Boudjelal et al 1997).…”

“…The fi rst member was called Stimulated with retinoic acid 13 (Stra13) (Boudjelal et al 1997) or Clast5 (Seimiya et al 2002) in mouse, Differentially Expressed in Chondrocytes (Dec1) (Shen et al 1997), E47 interacting protein 1 (Eip1) (Dear et al 1997) or Cytokine response gene 8 (CR-8) (Beadling et al 2001) in human, and Enhancer-ofSplit and Hairy-related protein-2 (Sharp-2) in rat (Rossner et al 1997). Similarly, the other member was called Sharp-1 in rat (Rossner et al 1997) and mouse (Azmi and Taneja, 2002) and Dec2 in human (Fujimoto et al 2001).…”

Stra13 regulates satellite cell activation by antagonizing Notch signaling

“…Stra13 expression is inducible by several stimuli in different cell types, and gain of function in cultured cells has demonstrated its role in the regulation of cellular differentiation, cell cycle arrest, stress response, and apoptosis. For instance, the overexpression of Stra13 in many cell types causes cell cycle arrest (Sun and Taneja, 2000; Beadling et al, 2001; Li et al, 2002; Seimiya et al, 2002) and promotes neurogenic and chondrogenic differentiation (Boudjelal et al, 1997; Shen et al, 2002) but inhibits adipogenesis (Yun et al, 2002). We have previously shown that Stra13-null mice exhibit defects in T cell activation, which leads to the development of a lupus-like autoimmune disorder (H. Sun et al, 2001) as well as defects in radiation-induced apoptosis (Thin et al, 2007).…”