A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers

How cell numbers are determined is not understood. Hedgehog-Gli activity is involved in precursor cell proliferation and stem cell self-renewal, and its deregulation sustains the growth of many human tumours. However, it is not known whether GLI1, the final mediator of Hh signals, controls stem cell numbers, and how its activity is restricted to curtail tumourigenesis. Here we have altered the levels of GLI1 and p53, the major tumour suppressor, in multiple systems. We show that GLI1 expression in Nestin+ neural progenitors increases precursor and clonogenic stem cell numbers in vivo and in vitro. In contrast, p53 inhibits GLI1-driven neural stem cell self-renewal, tumour growth and proliferation. Mechanistically, p53 inhibits the activity, nuclear localisation and levels of GLI1 and in turn, GLI1 represses p53, establishing an inhibitory loop. We also find that p53 regulates the phosphorylation of a novel N' truncated putative activator isoform of GLI1 in human cells. The balance of GLI1 and p53 functions, thus, determines cell numbers, and prevalence of p53 restricts GLI1-driven stem cell expansion and tumourigenesis

Chimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manner

Targeting stemness promises new therapeutic strategies against highly invasive tumors. While a number of approaches are being tested, inhibiting the core transcription regulatory network of cancer stem cells is an attractive yet challenging possibility. Here we have aimed to provide the proof of principle for a strategy, previously used in developmental studies, to directly repress the targets of a salient stemness and pluripotency factor: NANOG. In doing so we expected to inhibit the expression of so far unknown mediators of pro-tumorigenic NANOG function. We chose NANOG since previous work showed the essential requirement for NANOG activity for human glioblastoma (GBM) growth in orthotopic xenografts, and it is apparently absent from many adult human tissues thus likely minimizing unwanted effects on normal cells. NANOG repressor chimeras, which we name NANEPs, bear the DNA-binding specificity of NANOG through its homeodomain (HD), and this is linked to transposable human repressor domains. We show that in vitro and in vivo, NANEP5, our most active NANEP with a HES1 repressor domain, mimics knock-down (kd) of NANOG function in GBM cells. Competition orthotopic xenografts also reveal the effectiveness of NANEP5 in a brain tumor context, as well as the specificity of NANEP activity through the abrogation of its function via the introduction of specific mutations in the HD. The transcriptomes of cells expressing NANEP5 reveal multiple potential mediators of pro-tumorigenic NANEP/NANOG action including intercellular signaling components. The present results encourage further studies on the regulation of context-dependent NANEP abundance and function, and the development of NANEP-based anti-cancer therapies.This work was supported by a James McDonnell Brain Cancer Award, Fondation Eclosion funds and by the Département d’Instruction Publique de Genève to ARA. C.M. and M.K. were fellows of the ITN-EU networks CAPPELLA and HEALING, respectively

Regulation of Hedgehog Signalling Inside and Outside the Cell

The hedgehog (Hh) signalling pathway is conserved throughout metazoans and plays an important regulatory role in both embryonic development and adult homeostasis. Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The fatty nature of the Shh ligand means that it tends to associate tightly with the cell membrane, and yet it is known to act as a morphogen that diffuses to elicit pattern formation. Heparan sulfate proteoglycans (HSPGs) play a major role in the regulation of Hh distribution outside the cell. Inside the cell, the primary cilium provides an important hub for processing the Hh signal in vertebrates. This review will summarise the current understanding of how the Hh pathway is regulated from ligand production, release, and diffusion, through to signal reception and intracellular transduction

On a nonlinear flux--limited equation arising in the transport of morphogens

Motivated by a mathematical model for the transport of morphogenes in biological systems, we study existence and uniqueness of entropy solutions for a mixed initial-boundary value problem associated with a nonlinear flux--limited diffusion system. From a mathematical point of view the problem behaves more as an hyperbolic system that a parabolic one

Multi-graviton theory, a latticized dimension, and the cosmological constant

Beginning with the Pauli-Fierz theory, we construct a model for multi-graviton theory. Couplings between gravitons belonging to nearest-neighbor ``theory spaces'' lead to a discrete mass spectrum. Our model coincides with the Kaluza-Klein theory whose fifth dimension is latticized. We evaluate one-loop vacuum energy in models with a circular latticized extra dimension as well as with compact continuous dimensions. We find that the vacuum energy can take a positive value, if the dimension of the continuous space time is $6, 10,...$. Moreover, since the amount of the vacuum energy can be an arbitrary small value according to the choice of parameters in the model, our models is useful to explain the small positive dark energy in the present universe.Comment: 10 pages, No figure. Needs REVTeX4. citations are corrected and minor correction

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling

Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)–GLI signaling pathway is implicated in prostate cancer. We report expression of SHH–GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of GLI1(+)/PSA(+) primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH–GLI function and suggest a novel therapeutic approach