Research Report 2010 - MDC

Graduate StudentsRami Hamscho*Qingbin LiuBilyana StoilovaMagdalena Schmude*Undergraduate StudentsSusanne Eiglmeier*Julien Karriche*Francisca Leonard*Julia Tornack*Lina Zschockelt*Technical AssistantsCorinna BeckerKarolin FriedrichNatalie HaritonowMaria KnoblichSarah Schmidt*Ruth Zarmstorff*SecretariatSylvia Sibilak*part of the period reportedan important role of uORF-mediated translational controlin mammalian development and physiology.Nevertheless, genetic models in mammals are lackingto explore the physiological relevance of uORF-regulatedtranslation initiation.Truncated C/EBP isoforms sustain proliferation, whereasfull-length forms are inhibitors of cell division.Previously, we showed that anaplastic large cell lymphomaand Hodgkin Lymphoma express predominantlytruncated C/EBPβ. Rapamycin, an antibiotic thatinhibits mTOR signaling, shuts down the truncatedC/EBP isoform and concomitantly inhibits growth inboth types of lymphomas. Ectopic expression of truncatedC/EBPβ restored proliferation, suggesting thattruncated C/EBPβ represents a translationally controlledoncogene.By targeted recombination we have now generatedmouse C/EBPβ mutants that express distinct C/EBPβisoforms. The murine mutants revealed that C/EBPβisoform switching is important during liver regeneration,bone homeostasis and tumorigenesis. Mice deficientfor the C/EBPβ uORF initiation codon(C/EBPβ∆uORF) fail to initiate translation of the autoantagonistic,truncated “LIP” C/EBPβ isoform. Livers ofC/EBPβ∆uORF mice displayed defective regeneration.After partial hepatectomy, delayed and blunted entry ofhepatocytes into S-phase, persistent repression of E2Fregulatedgenes, and hyperactivation of acute phaseresponse genes became evident. Thus, switching to thetruncated isoform is important during liver regenerationand in shutting off acute phase response.C/EBPβ deficient mice and mice expressing only thetruncated “LIP” isoform (LIP knock-in mice, L/L) both displayincreased bone resorption. This is due to enhanceddifferentiation of the bone resorbing cell, the osteoclast.Failure to switch back to the long C/EBPβ isoformaugmented osteoclastogenesis. Indeed, ectopic expressionof the long isoform “LAP” in monocytes inhibitedformation of multi-nucleated osteoclasts. Rapamycin,an inhibitor of mTOR signaling that increases the “LAP”over “LIP” ratio, also inhibited osteoclastogenesis in wildModel of integrated control of osteoclastogenesis by C/EBPβ.Top to Bottom: Long (LAP) and truncated (LIP) C/EBPβ isoforms aregenerated from a single mRNA. The ratio between LAP and LIP is determinedby the activity of translation initiation factors, which are downstreamof growth factor, hormone, nutrient, and stress signaling pathways.The mammalian Target Of Rapamycin (mTOR) kinase integratesthese signals and plays an important role in adjusting the LAP/LIPratio (blue: low activity; red: high activity). The LAP isoform inducesMafB, an inhibitor of osteoclastogenesis that suppresses the activity ofseveral osteoclastic regulators (Mitf, Fos, NFATc1). Osteoclast precursorsthat lack C/EBP or that express LIP only, display strongly augmentedformation of giant osteoclasts that readily destroy bone substance.Cancer Research 91