A β-catenin/T cell factor-dependent transcriptional program is critical during cutaneous wound repair for the regulation of scar size; however, the relative contribution of β-catenin activity and function in specific cell types in the granulation tissue during the healing process is unknown. Here, cell lineage tracing revealed that cells in which β-catenin is transcriptionally active express a gene profile that is characteristic of the myeloid lineage. Mice harboring a macrophage-specific deletion of the gene encoding β-catenin exhibited insufficient skin wound healing due to macrophage-specific defects in migration, adhesion to fibroblasts, and ability to produce TGF-β1. In irradiated mice, only macrophages expressing β-catenin were able to rescue woundhealing deficiency. Evaluation of scar tissue collected from patients with hypertrophic and normal scars revealed a correlation between the number of macrophages within the wound, β-catenin levels, and cellularity. Our data indicate that β-catenin regulates myeloid cell motility and adhesion and that β-catenin-mediated macrophage motility contributes to the number of mesenchymal cells and ultimate scar size following cutaneous injury.

Expression of viral proteins causes important epigenetic changes leading to abnormal cell growth. Whether viral proteins directly target histone methyltransferases (HMTs), a key family enzyme for epigenetic regulation, and modulate their enzymatic activities remains elusive. Here we show that the E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro and in HPV-transformed HeLa cells. Furthermore, these three HMTs are required for E6 to attenuate p53 transactivation function. Mechanistically, E6 hampers CARM1- and PRMT1-catalyzed histone methylation at p53-responsive promoters, and suppresses the binding of p53 to chromatinized DNA independently of E6-mediated p53 degradation. p53 pre-methylated at lysine-372 (p53K372 mono-methylation) by SET7 protects p53 from E6-induced degradation. Consistently, E6 downregulates p53K372 mono-methylation and thus reduces p53 protein stability. As a result of the E6-mediated inhibition of HMT activity, expression of p53 downstream genes is suppressed. Together, our results not only reveal a clever approach for the virus to interfere with p53 function, but also demonstrate the modulation of HMT activity as a novel mechanism of epigenetic regulation by a viral oncoprotein.

Epstein-Barr virus (EBV) induces human B cell

HPV-16E7 is a major transforming protein, which has been implicated in the development of cervical cancer. The stability of E7 is thus important to ensure its fully functional status. Using the yeast two-hybrid system, we found that USP11 (ubiquitin-specific protease 11), a member of a protein family that cleaves polyubiquitin chains and/or ubiquitin precursors, interacts and forms a specific complex with HPV-16E7. Our results indicate that the USP11 can greatly increase the steady state level of HPV-16E7 by reducing ubiquitination and attenuating E7 degradation. In contrast, a catalytically inactive mutant of USP11 abolished the deubiquitinating ability and returned E7 to a normal rate of degradation. Moreover, USP11 not only protected E7 from ubiquitination but also influenced E7 function as a modulator of cell growth status. These results suggest that USP11 plays an important role in regulating the levels of E7 protein and subsequently affects the biological function of E7 as well as its contribution to cell transformation by HPV-16E7.Human papillomaviruses (HPVs) 3 have been etiologically linked to human cervical cancer (1). Much pathological evidence has indicated that persistent infections with specific high risk type HPVs (HPV-16, HPV-18, and several others) have a significant relationship with the formation of malignant tumors (2). HPVs are small, double-stranded DNA viruses that infect mucosal and cutaneous epithelial tissues. Since HPVs do not encode a viral DNA polymerase, these viruses are completely dependent on the host cell machinery for DNA replication except an origin-binding protein and a replicative DNA helicase (3). In order to provide all of the necessary cellular proteins required for viral replication, the virus has to keep its host cell in cycle, and this serves as the molecular basis for the proliferative phenotype of HPV lesions. The functions of two viral proteins, E6 and E7, from high risk type HPVs, are reflected in many of the cellular proteins with which they interact. Among a variety of cellular targets, the effects of E6 and E7 on p53 and pRb as well as on many other cellular proteins have been extensively investigated in the past. The results all point to significant alterations in the regulation of the cell cycle and apoptosis as well as chromosomal stability (4). However, a detailed mutagenesis study of E7 has also revealed that binding to Rb alone is not sufficient to cause cell transformation (5). It is clear that mutations in the carboxyl-terminal sequences of E7, outside the Rbbinding site, also severely impair the transformation function of E7 (6, 7). These results suggest that, aside from binding to Rb, other protein-protein interaction(s) are also necessary for the E7-mediated transformation.The HPV E7 protein is a small, rather acidic, polypeptide composed of nearly 100 amino acid residues. E7 is also short lived (8), and its degradation is regulated by the ubiquitin-proteasome pathway in cervical cancer cells (9, 10). The first 11 amino acid residues of E7 is the sign...

No abstract