In contrast, the mTOR complex 2 (mTORC2) contains, among others, mTOR, the rapamycininsensitive protein Rictor, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1). mTORC2 regulates the cytoskeleton and phosphorylates Akt (55). Its regulation is complex, but involves insulin, growth factors, serum, and nutrient levels.
Expression of Genes and Proteins
Regulation of genetic transcription and replication is crucial to the normal function of the daughter cells, the tissues and ultimately the organism. Transmission of external signals to the nucleus by way of the intracellular signal transduction cascade culminates in the transcription of specific genes and translation of the mRNA into proteins that ultimately affect the structure, function, and proliferation of the cell.
The human genome project resulted in the determination of the sequence of DNA of the entire human genome (56). With the completion of this project, it appears that the human haploid genome contains 23,000 protein coding genes. Sequencing the human genome is a major scientific achievement that opens the door for more detailed studies of structural and functional genomics. Structural genomics involves the study of three-dimensional structures of proteins based on their amino acid sequences. Functional genomics provides a way to correlate structure and function. Proteomics involves the identification and cataloging of all proteins used by a cell, and cytomics involves the study of cellular dynamics, including intracellular system regulation and response to external stimuli. The transcriptome is the set of all RNA molecules, including mRNA, rRNA, tRNA, and other noncoding RNA produced in one or a population of cells. The transcriptome varies with external environmental conditions and reﬂects the actively expressed genes. The metabolome describes a set of small-molecule metabolites, including hormones and signaling molecules, that are found in a single organism. Similar to the transcriptome and proteome, the metabolome is subject to rapid changes (57). The kinome of an organism describes a set of protein kinases, enzymes that are crucial for phosphorylation reactions.
Figure 6.8 Hereditary and sporadic cancer development based on the Knudson “two-hit” genetic model. All cells harbor one mutant tumor suppressor gene allele in hereditary cancer. The loss of the second allele results in the malignant phenotype.
Sporadic cancers develop in cells with normal genome, therefore requiring both alleles to be inactivated (two hits).
Cancer Genetics Cancer is a genetic disease that results from a series of mutations in various cancer genes. Uncontrolled cell growth occurs because of accumulation of somatic mutations or the inheritance of one or more mutations through the germline, followed by additional somatic mutations. The mutation in genes that are directly involved in normal cellular growth and proliferation can lead to the development of uncontrolled growth, invasion, and metastasis.
According to the Knudson hypothesis, which was first described in children with hereditary retinoblastoma, two hits or mutations within the genome of a cell are required for a malignant phenotype to develop (58). In hereditary cancers, the first hit is present in the genome of every cell. Only one additional hit is necessary, therefore, to disrupt the correct function of the second cancer gene allele. In contrast, sporadic cancers develop in cells without hereditary mutations in the cancer predisposing alleles. In this case, both hits must occur in a single somatic cell to disrupt both cancer gene alleles (Fig. 6.8).
Most adult solid tumors require 5 to 10 rate-limiting mutations to acquire the malignant phenotype. Among these mutations, some are responsible for causing the cancer phenotype, whereas others might be considered bystander mutations, as with, for example, the amplification of genes that are adjacent to an oncogene. The most compelling evidence for the mutagenic tumor development process is that the age-specific incidence rates for most human epithelial tumors increase at roughly the fourth to eighth power of elapsed time.