Hengst Ludger, Univ.Prof. Dr.

University / Clinic: Innsbruck Medical University
Institute: Biocenter, Division of Medical Biochemistry
Research Area: Cell Biology, Cancer Research, Medical Biochemistry

Email: ludger.hengst@i-med.ac.at
Web: www.i-med.ac.at/imcbc/medclinchemfolder/medclinchem.html

Research Topic:
The tumor suppressor p27Kip1 controls cell proliferation by binding to cyclin-dependent kinases (Cdks). Usually binding inactivates Cdks, but p27 can also assemble active cyclin D/Cdk complexes. In addition, p27 has Cdk-independent functions. Amongst those are regulation of cell motility, which links p27 to metastasis, and possibly regulation of apoptosis. Also in these processes, p27 was reported to exert both positive and negative effects. The multitude of p27 functions and the regulation of p27 by diverse signal transduction pathways indicate the existence of complex regulatory mechanisms. Consistently, p27 has long been known to be phosphorylated at distinct serine and threonine residues. Preliminary data suggest that additional modifications of p27 exist. Recently, we discovered such a novel p27 modification, tyrosine phosphorylation that impairs p27 Cdk inhibition (Grimmler et al., 2007; Chu et al., 2007). Since tyrosine phosphorylated p27 still binds to Cdks, it may be the underlying mechanism for p27's role as an assembly factor for active cyclin D/Cdk complexes in G1 phase. The spatial, temporal and functional characterisation of p27 modifications will be crucial for understanding the diverse and partially reverse p27 functions. Here we propose a systematic qualitative and quantitative analysis of p27 posttranslational modifications, their localisation, abundance and function during cell cycle progression and in growth arrest. In addition, we aim to identify modification-regulated assembly of specific p27 containing protein complexes in different compartments and cell cycle phases. We anticipate this work to contribute to the identification of pathways that can be selectively targeted in human malignancies to restore p27 as an inhibitor of cell proliferation and cell migration.

  The erythropoetin / p27 axis in erythroid cell proliferation and differentiation
details ...

Selected publications:
  Vosper J, Masuccio A, Kullmann M, Ploner C, Geley S, Hengst L
Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation
Oncotarget. 2015 Feb 20;6(5):2889-902

  Kullmann M, Grubbauer C, Goetsch K, Jäkel H, Podmirseg S, Trockenbacher A, Ploner C, Cato A, Weiss C, Kofler R, Hengst L
The p27-Skp2 axis mediates glucocorticoid-induced cell cycle arrest in T-lymphoma cells.
Cell Cycle 12 (16): 2625 - 2635.

  Höfer J, Schäfer G, Klocker H, Erb H, Mills I, Hengst L, Puhr M, Culig Z
PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21.
Am J Pathol. 2012 May;180(5):2097-107. Epub 2012 Mar 23.

  Jäkel H, Peschel I, Kunze C, Weinl C, Hengst L
Regulation of p27 (Kip1) by mitogen-induced tyrosine phosphorylation.
Cell Cycle 11(10): 1910-1917.

  Jäkel H, Weinl C, Hengst L
Phosphorylation of p27-Kip1by JAK2 directly links cytokine signaling to cell cycle control.
Oncogene, 30 (32): 3502 – 3512.

  Grespi F, Soratroi C, Krumschnabel G, Sohm B, Ploner C, Geley S, Hengst L, Häcker G, Villunger A
BH3-only protein Bmf mediates apoptosis upon inhibition of CAP-dependent protein synthesis
Cell Death Differ. 2010 Nov;17(11):1672-83

  Ecker K, Hengst L
Skp2: caugt in the Akt. Invited review.
Nature Cell Biology. 11, 377-379.

  Geley S, Hengst L
Zellzyklus. In: Die Onkologie.
2. Auflage. W. Hiddemann, Bartram C. R. (Eds.). Springer Verlag.

  Hengst L
Cell Proliferation and Restriction Point Control by the Tumour Suppressor p27Kip1.
Zellbiologie aktuell 35 (2), 10-14.

  Chu I, Hengst L, Slingerland J
The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Invited review.
Nature Reviews Cancer. 8, 253 - 267.

  Chu I, Sun J, Arnaout A, Kahn H, Hanna W, Narod S, Sun P, Keat-Tan C, Hengst L, Slingerland J
p27 phosphorylation by Src regulates inhibition of Cyclin E / Cdk2 and p27 proteolysis
Cell, 128, 281-294

  Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel E, Waddell M, Jäckel H, Kullmann M, Kriwacki R, Hengst L
The Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases
Cell, 128, 269 - 280

  Halfter H, Friedrich M, Resch A, Kullmann M, Stögbauer F, Ringelstein E, Hengst L
Oncostatin M induces growth arrest by inhibition of Skp2, Cks1, and cyclin A expression and induced p21 expression
Cancer Research 66, 6530-6539