Reflecting an increasing emphasis on collaborative science, the number of authors on published articles has markedly risen with time. With this trend, we see an increase in papers designating 2 or more co-first authors. To improve transparency in how such designations are made and reduce bias in the assignment of order, the JCI is now requiring an explanation for how the first-author position is determined when shared among contributing authors.
Abstract As described in Chapter 1, formation of the transcription initiation complex is required for Pol II transcription of protein-coding genes. This complex contains, in addition to the multiple subunits of Pol II, a set of general transcription factors that includes TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH (Table 14.1). These factors are involved in DNA-protein interactions (TFIID only); protein-protein interactions with Pol II, DNA binding transcriptional activators, and activator-bound coactivators; and enzymatic activities (DNA-dependent ATPase, DNA helicase, and protein kinase). In addition, TFIIH appears to play an essential role in both Pol II transcription and DNA repair processes (reviewed by Drapkin et al., 1994). (A complete description of DNA repair is beyond the scope of this book and interested readers should consult an authoritative text by Friedberg et al.[1995].) Among the many genes that encode components of the transcription initiation complex, germline mutations affecting only subunits of TFIIH have been identified as being responsible for hereditable human disorders.
The vascular endothelial growth factor is the target of the antiangiogenic drug bevacizumab. Another protein, placental growth factor, also represents a promising target for countering tumor angiogenesis.
The survival of metazoan organisms is dependent upon the utilization of O2 as a substrate for COX (cytochrome c oxidase), which constitutes Complex IV of the mitochondrial respiratory chain. Premature transfer of electrons, either at Complex I or at Complex III, results in the increased generation of ROS (reactive oxygen species). Recent studies have identified two critical adaptations that may function to prevent excessive ROS production in hypoxic cells. First, expression of PDK1 [PDH (pyruvate dehydrogenase) kinase 1] is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial enzyme that converts pyruvate into acetyl-CoA. In combination with the hypoxia-induced expression of LDHA (lactate dehydrogenase A), which converts pyruvate into lactate, PDK1 reduces the delivery of acetyl-CoA to the tricarboxylic acid cycle, thus reducing the levels of NADH and FADH2 delivered to the electron-transport chain. Secondly, the subunit composition of COX is altered in hypoxic cells by increased expression of the COX4-2 subunit, which optimizes COX activity under hypoxic conditions, and increased degradation of the COX4-1 subunit, which optimizes COX activity under aerobic conditions. Hypoxia-inducible factor 1 controls the metabolic adaptation of mammalian cells to hypoxia by activating transcription of the genes encoding PDK1, LDHA, COX4-2 and LON, a mitochondrial protease that is required for the degradation of COX4-1. COX subunit switching occurs in yeast, but by a completely different regulatory mechanism, suggesting that selection for O2-dependent homoeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms.
