YB-1 Is Important for Late-Stage Embryonic Development, Optimal Cellular Stress Responses, and the Prevention of Premature Senescence

Over the past decade, an increasing number of multifunctional regulatory factors that control gene expression at both the transcriptional and posttranscriptional levels have been described. Human YB-1 and its vertebrate homologues are one example. YB-1 belongs to a large family of proteins that contain a conserved nucleic acid-binding domain termed the cold shock domain (CSD), which shares about 40% amino acid sequence identity with bacterial cold shock proteins. Among the CSD family of proteins, YB-1 and its orthologues constitute an exceptionally conserved subfamily that contains nearly identical amino acid sequences for the whole molecule (>98% identity between the human and mouse proteins). While several members were initially identified as DNA-binding proteins that interacted specifically with a conserved cis-regulatory Y-box element, YB-1 proteins have since been shown to bind avidly in vitro to a wide variety of forms of nucleic acids, including pyrimidine-rich single-stranded DNA, triplex/single-stranded H-DNA, damaged DNA, and RNA (references 18 and 36 and references therein). Based on its broad nucleic acid-binding properties, a myriad of cellular functions have been ascribed to YB-1. In mammalian cells, YB-1 has been shown to shuttle between the nuclear and cytoplasmic compartments (reference 25 and references therein). Within the nucleus, YB-1 interacts directly with other DNA- and pre-mRNA-binding proteins such as p53, AP2, CTCF, hnRNP K, and SRp30c (for a complete list, see a recent review [20]). To date, YB-1 has been implicated in nuclear activities such as chromatin remodeling, transcriptional regulation, DNA repair, and pre-mRNA splicing/transport (11). YB-1 is also abundant in the cytoplasm, where it is a major structural component of messenger ribonucleoprotein complexes and may act as an mRNA chaperone (6, 9) and a regulator of translation (reference 1 and references therein). Thus, YB-1 has been proposed to function as a multifunctional coordinator for the control of gene expression in both the nucleus and the cytoplasm (20, 34). YB-1 is broadly expressed throughout development, and its expression level closely correlates with the cell proliferation state. YB-1 is abundantly expressed in early chicken and rat embryos, and its level decreases steadily during development (15, 19). High levels of YB-1 are also detected in vivo in actively proliferating adult tissues such as the colorectal epithelial glands (29) and regenerating liver tissue following chemical-induced damage (15) or hepatectomy (19). YB-1 is induced in various cell types in response to mitogenic stimuli, such as cytokine-stimulated T cells (27), serum-activated fibroblasts (19), and agonist-stimulated endothelial cells (31). Furthermore, increased nuclear and/or cytoplasmic expression of YB-1 has frequently been detected in a wide range of human cancers, including breast, ovarian, thyroid, and colorectal cancers, osteosarcomas, and synovial sarcomas (reviewed in reference 20). Similar results have also been described for experimental systems such as mouse and rabbit cancers (reviewed in reference 21). Importantly, an association of elevated levels of YB-1 and tumor progression has been reported for melanoma and also for lung, squamous cell, and prostate cancers (21). These clinical observations have suggested that disregulated expression of YB-1 may be associated with unfavorable clinical outcomes. However, it remains unclear whether YB-1 overexpression is causally related to the malignant phenotype or is simply a “marker” associated with rapid cell growth. Furthermore, the normal physiological role of YB-1 has yet to be defined, since knockout mice have been difficult to generate (28). To better understand the physiological functions of YB-1 in vivo, we created homozygous mice with a true null mutation in the YB-1 gene. An analysis of YB-1-deficient animals revealed that YB-1 is required for the normal development of multiple embryonic organ systems and for perinatal survival. YB-1 plays an important role in cellular stress responses and in the prevention of premature senescence in cultured primary cells. YB-1 is therefore essential for early mammalian development and important for cellular responses to a variety of stresses.