University of Cincinnati
Genome Research Institute
Department of Molecular Oncogenesis
GRI - D272
2180 E.Galbraith Road
Cincinnati,OH-45237

Phone - 513-558-8176

Email Patrick

Publications

Macroautophagy is a basic cellular process in which protein complexes and organelles are sequestered and targeted to the lysosomal compartment for destruction and recycling. In this way, macroautophagy can promote cell survival by providing nutrients during times of need and selectively destroying redundant or damaged organelles, such as mitochondria and portions of the endoplasmic reticulum. However, it is becoming clear that mis-regulation of macroautophagy can result in a variety of pathologies, including cancer, neurodegeneration and muscle degeneration. Therefore, it is important to understand how cellular stress signals communicate with elements of the macroautophagic machinery. Genetic screens in yeast identified a number of gene products necessary for the induction of different forms of macroautophagy induced in a variety of yeast species. In combination, these screens have identified 27 genes that have been denoted ATG1-27 (for autophagy-related) under a newly adopted nomenclature, and have led to the discovery of numerous mammalian orthologues. Of these orthologues, two have stood out as belonging to potential signaling pathways important for the regulation of mammalian macroautophagy. The mammalian orthologue of Atg6p is the Bcl-2 binding protein, beclin-1, that positively regulates macroautophagy by interacting with the class III PI3K, Vps34. The only protein kinase to be identified in the yeast genetic screens was a serine/threonine kinase, termed Atg1, and two Atg1p orthologues have been identified in mammals and termed ULK1 and 2 (for Unc-51-Like Kinase). My research interest is to study how cellular stress signals regulate mammalian macroautophagy through beclin 1 and the ULKs. A major part of this research has been to develop new biochemical assays for the measurement of macroautophagy induction. Using known macroautophagy substrates as well as newly-created artificial substrates, novel assays are being developed that are capable of measuring the end-point of the macroautophagic process ie. lysosomal-based, proteolytic cleavage of the substrate.


Publications

1:	Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site. J Biol Chem. 2002 May;277(22):20104-12. PMID: 11914378 [PubMed - indexed for MEDLINE]

2:	Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G Mammalian TOR: a homeostatic ATP sensor. Science. 2001 Nov;294(5544):1102-5. PMID: 11691993 [PubMed - indexed for MEDLINE]

3:	Dennis PB, Pullen N, Pearson RB, Kozma SC, Thomas G Phosphorylation sites in the autoinhibitory domain participate in p70(s6k) activation loop phosphorylation. J Biol Chem. 1998 Jun;273(24):14845-52. PMID: 9614086 [PubMed - indexed for MEDLINE]

4:	Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G Phosphorylation and activation of p70s6k by PDK1. Science. 1998 Jan;279(5351):707-10. PMID: 9445476 [PubMed - indexed for MEDLINE]

5:	Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. EMBO J. 1997 Jun;16(12):3693-704. PMID: 9218810 [PubMed - indexed for MEDLINE]

6:

von Manteuffel SR, Dennis PB, Pullen N, Gingras AC, Sonenberg N, Thomas G The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k. Mol Cell Biol. 1997 Sep;17(9):5426-36. PMID: 9271419 [PubMed - indexed for MEDLINE]

7:	Moser BA, Dennis PB, Pullen N, Pearson RB, Williamson NA, Wettenhall RE, Kozma SC, Thomas G Dual requirement for a newly identified phosphorylation site in p70s6k. Mol Cell Biol. 1997 Sep;17(9):5648-55. PMID: 9271440 [PubMed - indexed for MEDLINE]

8:	Dennis PB, Pullen N, Kozma SC, Thomas G The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol Cell Biol. 1996 Nov;16(11):6242-51. PMID: 8887654 [PubMed - indexed for MEDLINE]

9:	Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, Thomas G The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J. 1995 Nov;14(21):5279-87. PMID: 7489717 [PubMed - indexed for MEDLINE]

10:	Han JW, Pearson RB, Dennis PB, Thomas G Rapamycin, wortmannin, and the methylxanthine SQ20006 inactivate p70s6k by inducing dephosphorylation of the same subset of sites. J Biol Chem. 1995 Sep;270(36):21396-403. PMID: 7545671 [PubMed - indexed for MEDLINE]

11:	Benner GE, Dennis PB, Masaracchia RA Activation of an S6/H4 kinase (PAK 65) from human placenta by intramolecular and intermolecular autophosphorylation. J Biol Chem. 1995 Sep;270(36):21121-8. PMID: 7673144 [PubMed - indexed for MEDLINE]

12:	Dennis PB, Masaracchia RA Activation of an S6 kinase from human placenta by autophosphorylation. J Biol Chem. 1993 Sep;268(26):19833-41. PMID: 8366121 [PubMed - indexed for MEDLINE]

13:	Dennis PB, Brandon SD, Masaracchia RA Site-specific phosphorylation of a synthetic peptide derived from ribosomal protein S6 by human placenta protein kinases. Biochem Biophys Res Commun. 1990 Dec;173(2):673-9. PMID: 2260978 [PubMed - indexed for MEDLINE]