Table of Contents

June 2003; 3 (4)

Speaking of Pharmacology



  • Advances in cancer research have exploited the knowledge that mutations in proto-oncogenes and/or mutations in both alleles of tumor suppressor genes can bring about the cancer phenotype. Research originating from the opposite side of the coin—cancer-resistance genetics—has been less spectacular. Nonetheless, Cui et al. have observed one BALB/c mouse that did not bear tumors after receiving repeated injections of highly aggressive tumor cells. After breeding a colony of cancer-resistant mice from the resistant founder, the authors found that the trait was inherited in simple Mendelian dominant fashion, most likely under the control of a single locus. Intriguingly, this resistance trait disappears with age.

  • The protein kinase mTOR (mammalian target of rapamycin) promotes cell growth by phosphorylating substrates leading to the derepression of mRNA translation. Recently, a number of mTOR-interacting proteins (such as Raptor and GβL) have been characterized, shedding light on the pathway that regulates protein expression and cell growth. Unfortunately, conflicting results have obfuscated the roles of these proteins within the context of the mTOR signaling pathway. Other proteins, such as the tuberous sclerosis complex proteins (TSCs), appear to inhibit the activity of mTOR and thereby prevent the activation of the p70S6 kinase and the eukaryotic initiation factor 4E-binding protein 1. Mutations of mTOR-inhibiting TSCs have in fact been implicated in disease, underscoring the importance of further elucidating the mTOR pathway.


  • Of the nearly sixty P450s expressed in humans all but fifteen are involved in the metabolism of xenobiotics, vitamins, sterols, fatty acids, or eicosanoids. P450 polymorphisms (i.e., variations in the expression of particular P450 enzymes) arise from gene mutations or duplications, induction or repression of P450 activity, or differences in kinetic activity (based on amino acid substitutions resulting from polymorphisms). As such, P450 polymorphisms can have a profound effect on an individual’s response to drug clearance and pharmacokinetics, to the balance of endogenous compounds, and to onset or severity of disease states.

  • Three groups of K+ channels have been identified: voltage-gated, inwardly rectifying, and weakly rectifying. The weakly rectifying K+ channels, which are open at rest and exhibit little time- or voltage-dependence, comprise dimers of subunits, each of which contains four transmembrane domains and two pore domains. Within this family of weakly rectifying channels, the TASK channels are known to be sensitive to acidic pH, hypoxia, temperature changes, and volatile anesthetics. Evidence suggests that the subunits TASK-1 and TASK-3 might form heterodimers, in addition to homodimers, allowing for channels with intermediate properties. What tasks, ahem, these channels participate in are discussed.

  • A variety of chemical modifications of chromatin—that is, modification of protein as well as nucleic acid—are involved in regulating gene function. When the nuclear program that coordinates these modifications goes awry, multiple genes could be aberrantly expressed, although their protein-coding sequences would appear normal. “Multigenic” diseases could thus go undetected despite even the most thorough search for protein polymorphisms. Evidence is accumulating that schizophrenia may arise from the abnormal epigenetic regulation of multiple genes, and an appreciation of the epigenetic factors that culminate in disease may be key in developing effective therapies.

Beyond the Bench