Gene Activation and Inactivation

In some cases, hemoglobin F may remain elevated (Weatherall et al., 1976). Thus, in sickle cell anemia, hemoglobin F is elevated (10-30% in Saudi Arabians, but generally 5% in all other individuals with sickle cell anemia), as it is also in /3-thalassemia (where it may represent from 10 to 100% of the total hemoglobin). It has been postulated that some of this increase may result from an increase in the total mass of erythropoietic tissue. 

Hemoglobin F production may increase in pregnancy, leukemia (especially juvenile chronic myeloid leukemia), aplastic anemia, and in a few other disorders (Weatherall, 1976). 

Neoplastic tissues are capable of producing a variety of proteins, enzymes, and hormones that are not produced by the tissues from which the neoplasm arose. It is believed that the neoplastic process results in the activation of certain genes that otherwise would have remained inactive. Thus, in juvenile chronic myeloid leukemia, hemoglobin F gradually increases in the red blood cells, which also assume 

An analysis of the activation-inactivation of the gene for tyrosine aminotransferase has been made in rat hepatoma cell cultures (Martin and Tomkins, 1970). It is known that the synthesis of tyrosine aminotransferase can be induced by glucocorticoids during the latter half of the Gi and S periods of the cell cycle but not during the G2 or early part of the Gi periods. Although the mechanism that is postulated is complex, it involves, in part, the activation and inactivation of genes regulating the synthesis of tyrosine aminotransferase. 

In cultured mammalian cells, thymidine kinase activity is low during the Gi period and increases at the start of the S period of the cell cycle (Stubblefield and Murphree, 1967 Loeb et al., 1970), reaches a maximum during the S period, remains elevated through the G2 period, and decreases abruptly at the end of mitosis (Stubblefield and Murphree, 1967 Thilly et al., 1975 Howard et al., 1974 Bello, 1974). This would appear to represent activation-inactivation of the gene for thymidine kinase. 

---

During the cell cycle, chromosome structures shuttle between de-condensed interphase and condensed mitosis states. Dynamic changes also occur at the lower levels of architectures, i.e., at the chromatin and nucleosome levels. Upon gene activation and inactivation, folding and unfolding of the nucleosome structure and the chromatin fibers occur at limited loci of the genome. Namely, the structures of the chromosome are dynamic and mobile. Nevertheless, there are basic structural units that remain stable and constitute the fundamental chromosome architecture. 

Aldred MA, Trembath RC. Activating and inactivating mutations in the human GNAS1 gene. Hum Mutat 2000 16[3] 183—189. 

A considerable number of transcription factors have reactive cysteine residues, which enable them to respond to the redox conditions in the cell. Since cadmium perturbs redox homeostasis, it can affect this class of transcription factors. If cadmium can displace the tetra-coordinate zinc atoms in zinc finger-containing transcription factors, it will affect them as well. Many of the pathways involving activation and inactivation of transcription factors involve kinases and phosphatases, themselves under the intricate control of calcium fluxes. It is therefore no surprise that cadmium will exert effects on the activity of transcription factors, the activation of proto-oncogenes, and thereby on gene expression (Figure 20.8i and i ). 

The mechanisms involved in gene aclivatinn and inactivation are major problems in biology, so that transient, or permanent structures associated with such phenomena will continue to attract much attention. There is now evidence for changes in chromatin structure at chromosome sites prior to their becoming transcriptionally active nuclease sensitive sites, enhancers, and promolerx have also been identified at various loci. 

Among all channels, the Ky family is the most diverse, with pronounced mechanisms of activation and inactivation (see earlier, and Figure 16.6A). This family is represented by 40 different genes (Table 16.6), each Ky gene encoding a 6TM subunit, four of which form a functional channel tetramer (Figure 16.4). 

Activation and inactivation of Gene Expression Using RNA Sequences... 

Constant vital functions thus frequently need to have at their disposal several editions of a given type of genes in several regions of the genome that are successively activated and inactivated, or vice versa, with respect to protein-synthesizing ability. This view is advanced as an explanation of the generality of the most important types of major-component multiplicity in proteins. These types are on the one hand the successive embryonic and adult editions of a protein and on the other hand the different editions found at any one time in different tissues of the same animal. The latter type of protein heterogeneity has been referred to earlier and may be interpreted in the same terms. In each tissue the particular intracellular... 

Our question concerning the causes of differential gene activity is thus a question of which factors activate and inactivate the genes. We... 

Acetylation of histones H3 and H4 is associated with the activation or inactivation of gene transcription (Chapter 37). 

Our studies of the ERT cell cycles show that they are regulated by nutrition (Britton Edgar 1998). If the newly hatched larva is starved for dietary amino acids, DNA replication in most ERTs is not initiated. Under starvation conditions these tissues express low levels of cyclin E and E2F, the transcription factor which is probably responsible for cyclin E expression. If either E2F or cyclin E is induced in starved larvae, DNA replication in the ERTs is activated, and thus expression of these genes appears to limit the ERT cell cycle. When nutrient-deprived larvae are fed, expression of E2F and cyclin E mRNAs increases approximately sixfold, and DNA replication is initiated in most ERT cells. If the animal is first fed and then starved, the ERT cell cycle is activated and then inactivated quite rapidly. These experiments all indicate that the ERT cell cycle is nutrition-responsive, rather than controlled by a rigid developmental program. 

---