Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets

Dlk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair

Summary: Lung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering ∼95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudomonas aeruginosa-induced acute lung injury in mice, that non-canonical Notch ligand Dlk1 (delta-like 1 homolog) is essential for AT2-to-AT1 differentiation. Notch signaling was activated in AT2 at the onset of repair but later suppressed by Dlk1. Deletion of Dlk1 in AT2 induced persistent Notch activation, resulting in stalled transition to AT1 and accumulation of an intermediate cell population that expressed low levels of both AT1 and AT2 markers. Thus, Dlk1 expression leads to precisely timed inhibition of Notch signaling and activates AT2-to-AT1 differentiation, leading to alveolar repair. : Finn et al. show that Notch signaling is activated in type II cells after alveolar injury but that subsequent Dlk1-mediated inhibition of Notch is required for complete type II-to-type I cell transition and alveolar repair. Thus, Dlk1 and Notch are potential therapeutic targets for treatment of lung injury. Keywords: lung, alveoli, progenitor type II cell, Notch, Dlk

MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia

Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the develo

UV resonance Raman investigation of the conformations and lowest energy allowed electronic excited states of tri- and tetraalanine: Charge transfer transitions

UV resonance Raman excitation profiles and Raman depolarization ratios were measured for trialanine and tetraalanine between 198 and 210 nm. Excitation within the π → π* electronic transitions of the peptide bond results in UVRR spectra dominated by amide peptide bond vibrations. In addition to the resonance enhancement of the normal amide vibrations, we find enhancement of the symmetric terminal COO- vibration. The Ala3 UVRR AmIII3 band frequencies indicate that poly-proline II and 2.5 1 helix conformations and type II turns are present in solution. We also find that the conformation of the interior peptide bond of Ala4 is predominantly poly-proline-II-like. The Raman excitation profiles of both Ala3 and Ala4 reveal a charge transfer electronic transition at 202 nm, where electron transfer occurs from the terminal nonbonding carboxylate orbital to the adjacent peptide bond π* orbital. Raman depolarization ratio measurements support this assignment. An additional electronic transition is found in Ala4 at 206 nm. © 2010 American Chemical Society

UV resonance raman investigation of electronic transitions in α-helical and polyproline II-like conformations

UV resonance Raman (UVRR) excitation profiles and Raman depolarization ratios were measured for a 21-residue predominantly alanine peptide, AAAAA(AAARA)3A (AP), excited between 194 and 218 nm. Excitation within the π→π* electronic transitions of the amide group results in UVRR spectra dominated by amide vibrations. The Raman cross sections and excitation profiles provide information about the nature of the electronic transitions of the α-helix and polyproline II (PPII)-like peptide conformations. AP is known to be predominantly a-helical at low temperatures and to take on a PPII helix-like conformation at high temperatures. The PPII-like and a-helix conformations show distinctly different Raman excitation profiles. The PPII-like conformation cross sections are approximately twice those of the a-helix. This is due to hypochromism that results from excitonic interactions between the NV1 transition of one amide group with higher energy electronic transitions of other amide groups, which decreases the α-helical NV1 (π→π*) oscillator strengths. Excitation profiles of the α-helix and PPII-like conformations indicate that the highest signal-to-noise Raman spectra of a-helix and PPII-like conformations are obtained at excitation wavelengths of 194 and 198 nm, respectively. We also see evidence of at least two electronic transitions underlying the Raman excitation profiles of both the a-helical and the PPII-like conformations. In addition to the well-known ∼190 nm π→π* transitions, the Raman excitation profiles and Raman depolarization ratio measurements show features between 205-207 nm, which in the a-helix likely results from the parallel excitonic component. The PPII-like helix appears to also undergo excitonic splitting of its π→π* transition which leads to a 207 nm feature. © 2008 American Chemical Society