The epidermis is a stratified, continually renewing epithelium dependent on a balance among cell proliferation, differentiation, and death for homeostasis. In normal epidermis, a mitotically active basal layer gives rise to terminally differentiating keratinocytes that migrate outward and are ultimately sloughed from the skin surface as enucleated squames. Although many proteins are known to function in maintaining epidermal homeostasis, the molecular coordination of these events is poorly understood. RIP4 is a novel RIP (receptor-interacting protein) family kinase with ankyrin repeats cloned from a keratinocyte cDNA library. RIP4 deficiency in mice results in perinatal lethality associated with abnormal epidermal differentiation. The phenotype of RIP4(-/-) mice in part resembles that of mice lacking IKKalpha, a component of a complex that regulates NF-kappaB. Despite the similar keratinocyte defects in RIP4- and IKKalpha-deficient mice, these kinases function in distinct pathways. RIP4 functions cell autonomously within the keratinocyte lineage. Unlike IKKalpha, RIP4-deficient skin fails to fully differentiate when grafted onto a normal host. Instead, abnormal hair follicle development and epidermal dysplasia, indicative of progression into a more pathologic state, are observed. Thus, RIP4 is a critical component of a novel pathway that controls keratinocyte differentiation.
High throughput sequencing of a mouse keratinocyte library was used to identify an expressed sequence tag with homology to the epidermal growth factor (EGF) family of growth factors. We have named the protein encoded by this expressed sequence tag Epigen, for epithelial mitogen. Epigen encodes a protein of 152 amino acids that contains features characteristic of the EGF superfamily. Two hydrophobic regions, corresponding to a putative signal sequence and transmembrane domain, flank a core of amino acids encompassing six cysteine residues and two putative N-linked glycosylation sites. Epigen shows 24 -37% identity to members of the EGF superfamily including EGF, transforming growth factor ␣, and Epiregulin. Northern blotting of several adult mouse tissues indicated that Epigen was present in testis, heart, and liver. Recombinant Epigen was synthesized in Escherichia coli and refolded, and its biological activity was compared with that of EGF and transforming growth factor ␣ in several assays. In epithelial cells, Epigen stimulated the phosphorylation of c-erbB-1 and mitogen-activated protein kinases and also activated a reporter gene containing enhancer sequences present in the c-fos promoter. Epigen also stimulated the proliferation of HaCaT cells, and this proliferation was blocked by an antibody to the extracellular domain of the receptor tyrosine kinase c-erbB-1. Thus, Epigen is the newest member of the EGF superfamily and, with its ability to promote the growth of epithelial cells, may constitute a novel molecular target for wound-healing therapy.
The p53 tumor suppressor plays a major role in preventing tumor development by transactivating genes to remove or repair potentially tumorigenic cells. Here we show that the Y-box-binding protein, YB1, acts as a negative regulator of p53. Using reporter assays we show that YB1 represses transcription of the p53 promoter in a sequence-specific manner. We also show that YB1 reduces endogenous levels of p53, which in turn reduces p53 activity. Conversely, inhibiting YB1 in a variety of tumor cell lines induces p53 activity, resulting in significant apoptosis via a p53-dependent pathway. These data suggest that YB1 may, in some situations, protect cells from p53-mediated apoptosis, indicating that YB1 may be a good target for the development of new therapeutics.Apoptosis, or programmed cell death, is the mechanism by which damaged, modified or superfluous cells are removed from a complex organism (1). Another important role for apoptosis is preventing the development of cancer by removing cells with mutated or damaged DNA in order to preserve the integrity of the genome (2). The tumor suppressor protein p53 plays a pivotal part in this and consequently has been termed the "guardian of the genome" (2). In response to DNA damage, p53 is "activated" and initiates either growth arrest or apoptosis pathways (3). This allows DNA damage to be repaired or potential tumor precursor cells to be removed from tissues. Both pathways are initiated probably via the transcriptional activation of specific genes by p53. These genes include p21 WAF1/CIP1 (4), GADD45 (5), and 14-3-3 (6), which induce cell cycle arrest, and Bax (7), killer/DR5 (8), and PIG3 (9), which induce apoptosis.Consistent with its important tumor suppressor role, more than 50% of human cancers contain mutations in the p53 gene, encoding a protein that is inactive for some or all of the functions of p53 (10). In the other 50% of cancers there is selection against other components of the p53 signaling pathway, suggesting that p53 may be functionally inactive in the vast majority of cancers. Thus, there appears to be a powerful selection against functional p53 during tumor development.The Y-box-binding protein, YB1, belongs to the family of cold shock proteins, which is highly conserved from bacteria to man. YB1 is multifunctional and appears to regulate gene expression at both the transcriptional and translational levels (11,12). With regard to transcription, we noticed that YB1 regulates some of the same genes as wild type (wt) 1 p53 (13-19) but in an opposing manner. For example, the fas gene promoter is repressed by YB1 (13) and stimulated by wt p53 (19), whereas the multidrug resistance (mdr1) gene promoter is activated by YB1 (14) and repressed by wt p53 (16). These data suggest that YB1 might negatively regulate p53.In this study we present evidence that YB1 represses the p53 promoter and down-regulates endogenous p53 expression. We then show that a reduction of YB1 in several tumor cell lines results in an induction of apoptosis via the activation of a ...
A novel alpha-chemokine, designated KS1, was identified from an EST database of a murine immature keratinocyte cDNA library. The EST has 94% similarity to a recently cloned human gene, BRAK, that has no demonstrated function. Northern analysis of mouse and human genes showed detectable mRNA in brain, intestine, muscle and kidney. Tumour panel blots showed that BRAK was down-regulated in cervical adenocarcinoma and uterine leiomyoma, but was up-regulated in breast invasive ductal carcinoma. KS1 bound specifically to B cells and macrophages, as well as two B cell lines, CESS and A20, and a monocyte line, THP-1. KS1 showed no binding to naive or activated T cells. In addition, KS1 stimulated the chemotaxis of CESS and THP-1 cells but not T cells. The s.c. injection of KS1 creates a mixed inflammatory response in Nude and C3H/HeJ mice. The above data indicates that KS1 and its human homologue represents a novel non-ELR alpha-chemokine that may have important roles in trafficking of B cells and monocytes. We propose the name B cell- and monocyte-activating chemokine (BMAC) for this molecule to reflect the described biological functions.
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