The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells.

HMG1 (high mobility group 1) is a ubiquitous and abundant chromatin component. However, HMG1 can be secreted by activated macrophages and monocytes, and can act as a mediator of inflammation and endotoxic lethality. Here we document a role of extracellular HMG1 in cell migration. HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays. HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells. These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses. Pertussis toxin and the mitogen-activated protein kinase kinase inhibitor PD98059 also blocked HMG1-induced rat smooth muscle cell migration, suggesting that a G(i/o) protein and mitogen-activated protein kinases are required for the HMG1 signaling pathway. We also show that HMG1 can be released by damage or necrosis of a variety of cell types, including endothelial cells. Thus, HMG1 has all the hallmarks of a molecule that can promote atherosclerosis and restenosis after vascular damage.

Cancer epigenetics: from disruption of differentiation programs to the emergence of cancer stem cells.

Cancer is a disease of the genome. Whereas efforts to understand the molecular basis of cancer have in the past largely focused on the role of mutations, recent evidence points to a strong epigenetic component in tumorigenesis, and epigenetic defects have been linked to loss of cell cycle control and cell survival. Here, we discuss the possibility that epigenetic alterations may promote tumor formation by an alternative mechanism. We speculate that epigenetic changes in stem cells and somatic cells contribute significantly to carcinogenesis by disruption of cellular differentiation programs. Epigenetic interference and loss of cellular identity may be particularly relevant for the emergence of cancer stem cells.

Spatially precise DNA bending is an essential activity of the sox2 transcription factor.

Sox proteins, a subclass of high mobility group box proteins, govern cell fate decisions by acting both as classical transcription factors and architectural components of chromatin. We aimed to demonstrate that the DNA bending activity of Sox proteins is essential to regulate gene expression. We focused on mouse Sox2, which participates in the transactivation of the Fgf4 (fibroblast growth factor 4) gene in the inner cell mass of the blastocyst. We generated six substitutions in the high mobility group box of Sox2. One mutant showed a reduced DNA bending activity on the Fgf4 enhancer (46 degrees instead of 80 degrees), which resulted in more powerful transactivation compared with the wild type protein. We then selected two single-base mutations in the Fgf4 enhancer that make the DNA less bendable by the Sox2 protein. Again, a different DNA bend (0 degrees and 42 degrees instead of 80 degrees) resulted in a different activation of transcription, but in this case reduced bending corresponded to decreased transcription. We found that the opposite effect on transcription of similar DNA bending angles is due to a 20 degrees difference in the relative orientation of the DNA bends, proving that a correct three-dimensional geometry of enhanceosome complexes is necessary to promote transcription.