Ets proteins in biological control and cancer

Abstract

The Ets family consists of a large number of evolutionarily conserved transcription factors, many of which have been implicated in tumor progression. Extensive studies on this family of proteins have focused so far mainly on the biochemical properties and cellular functions of individual factors. Since most of the Ets factors can bind to the core consensus DNA sequence GGAA/T in vitro, it has been a challenge to differentiate redundant from specific functions of various Ets proteins in vivo. Recent findings, however, suggest that such apparent redundancy may in fact be a central component of a network of differentially regulated specific Ets factors, resulting in distinct biological and pathological consequences. The programmed "Ets conversion" appears to play a critical role during tumor progression, especially in control of cellular changes during epithelial-mesenchymal transition and metastasis. Coordination of multiple Ets gene functions also mediates interactions between tumor and stromal cells. As such, these new insights may provide a novel view of the Ets gene family as well as a focal point for studying the complex biological control involved in tumor progression. KeywordsEts; transcriptional regulation; ECM; cancer; invasion; metastasis; EMT; epithelium; stroma The Ets family of proteins consists of a large number of evolutionarily conserved transcription factors. There are 25 human and 26 murine Ets family members. Ets factors control specific genes that perform critical roles in diverse processes, including cell proliferation, apoptosis, differentiation, lymphoid cell development, angiogenesis, and invasiveness [Sementchenko and Watson, 2000]. To date, studies in the field have largely focused on individual Ets factors and have indeed yielded valuable, albeit fragmented, information. Recent findings, on the other hand, have suggested that several Ets factors may participate in a coordinated program that modulates cell migration and invasiveness, thus affecting tumor progression toward metastasis. In this review, we will examine the recent progress in Ets biology and provide a forum for discussion on a systemic view of Ets functions. Detailed descriptions of Ets proteins and their functions have been provided in several recent reviews [Watson and Seth, 2000;Watson et al., 2001;Dittmer, 2003;Oikawa and Yamada, 2003].Cancer results from a multi-step series of genetic changes that lead to essential alterations in cell physiology such as loss of growth controls and normal apoptotic response as well as sustained angiogenesis, invasion, and metastasis [Hanahan and Weinberg, 2000]. While it is known that most human tumors are derived from epithelial cells that have undergone multiple genetic alterations [Hanahan and Weinberg, 2000], it is also becoming clear that the alterations

ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK

“…28,29 Its expression is highly regulated by the v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1) in invasive breast cancer cells. 30 Here, we have shown that Ets-1 was significantly (Po0.01) downregulated by ERp29 (Figure 2a), further supporting a mechanistic link of ERp29 in attenuating uPAR in these slowly proliferating ERp29-transfected cells. Given that activation or loss of the uPAR-b 1 -integrin-EGFR complex decides the fate of the cell between proliferation and growth arrest (Figure 1), we further investigated whether ERp29-mediated cell growth arrest in MDA-MB-231 cells was associated with the interruption of downstream signaling regulated by this complex.…”

PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression

“…As shown in Figure 4a, western blot analyses revealed that rPAUF activated p90RSK, a downstream effector of the ERK signaling cascade (Anjum and Blenis, 2008), and subsequently the p90RSK target transcription factors, CREB and ELK-1. ELK-1 is known to be activated by the ERK and JNK signaling pathways (Hsu et al, 2004). The transcription factors c-Jun and ATF2, which are downstream targets of JNK signaling cascade, were also activated.…”

SP100 expression modulates ETS1 transcriptional activity and inhibits cell invasion

“…Ets proteins constitute a family of conserved sequencespecific transcription factors and share an 85 amino-acid DNA-binding domain, the ETS domain (Graves and Petersen, 1998;Watson et al, 2002;Hsu et al, 2004). Ets factors bind to the GGAA/T core motif (Ets-binding site, EBS) in the enhancer or promoter regions of their target genes (Sementchenko and Watson, 2000;Dittmer, 2003;Obika et al, 2003).…”