Chemistry of Life: 02/1990

regulation : alternative splicing : epigenetics : gene regulation : nonsense-mediated decay : nonstop decay : response elements : RNA processing : spliceosome : transcription : transcription factors : transcription initiation : termination of transcription

Gene regulation ensures that the genes of differentiated, somatic cell lines are normally repressed, and are only expressed when their products are required. Failure of gene regulation and uncontrolled proliferation is a feature of malignancies and arises through carcinogenic mutations.

Gene induction permits gene expression (derepression), and gene induction mechanisms ultimately involve regulatory proteins that bind to a regulatory DNA gene locus to induce or upregulate gene expression, which involves transcription, pre-mRNA splicing, and translation. Other regulatory proteins bind to repressor sequences to downregulate gene expression. Regulatory proteins bind to segments of DNA and bring about gene regulation. Most gene regulation proteins are single proteins, often homodimers or homotetramers, which bind to two ligands: a. a metabolic intermediate, and b. a cis-acting gene regulation element. Trans-acting factors are usually protein factors control gene expression by binding to cis-acting sequences, which are DNA sequences in the vicinity of the structural portion of a gene, and which are required for gene expression. Regulatory proteins are targetted for early degradation at the proteasome by the ubiquitin-mediated protein degradation pathway. Some control of gene expression is tissue-specific and other control mechanisms are pleiotropic because they affect varied tissues.

Proto-oncogenes promote cell proliferation – these are genes coding for growth factors, transcription factors, and trans-membrane receptors for signal transduction by growth factors, and estrogens. Oncogenes are mutated proto-oncogenes, which drive excessive cell proliferation in the absense of tumor suppressors.

Defective RNAs are removed by nonsense-mediated decay and RNA is continuously degraded by nonstop decay. Apoptosis is essential, programmed cell death. Sublethal stressors cause repression of housekeeping genes and activation of stress genes that code for stress proteins and molecular chaperones. Heat shock response is an important homeostatic mechanism that enables cells to survive a variety of environmental stresses. These heat shock proteins function in multi-protein complexes as molecular chaperones and assist in the proper protein folding of stress damaged proteins, and stabilization of other cellular proteins. Severely damaged proteins are degraded. When DNA is damaged, cell-cycle checkpoints employ signal transduction pathways to arrest the cell cycle, pending repair. If damage to DNA or proteins is too severe, apoptosic pathways are activated.

Regulation of metabolism is primarily determined by separation of enzymes and metabolites in separate compartments, by feedback control of activity (allosteric) or synthesis of inducible/repressible enzymes. Chemical cofactors are non-proteinaceous substances that assist enzymes in performing catalytic actions. Molecular genetic cofactors are activators or repressors.