Therapeutic considerations of PARP in stem cell biology: Relevance in cancer and beyond.

Cancer stem cells (CSCs) are of fundamental importance in tumor progression because of their tumor-initiating properties, their resistance to radio- and chemotherapy, their invasive properties and their propensity to escape immune responses that together contribute to tumor relapse. These highly aggressive features underscore the importance of constantly identifying new and innovative therapeutic solutions to eradicate these cells. In this narrative review we discuss recent findings on the involvement of PARP family members in cancer stem cell biology and the benefit of their inhibition. Nonetheless, an important limitation in the use of PARP inhibitors is the emergence of a prominent function of PARP1 in non-cancer stem cell biology including stem cell maintenance and differentiation during development, neurogenesis or adipogenesis. Thus, we also summarize the dominant discoveries revealing the importance of PARP1 in normal stem cell biology.

Low serum high-density lipoprotein cholesterol in childhood is associated with adolescent asthma.

BACKGROUND: Whilst emerging evidence from animal and cell experiments has shown high-density lipoprotein cholesterol to have anti-inflammatory effects consistent with a protective role in asthma, human studies investigating the relationship of high-density lipoprotein cholesterol with asthma have produced conflicting results. OBJECTIVE: To examine the association between serum lipids among Cypriot children aged 11-12 years and prevalence of asthma at age 15-17 years. METHODS: In 3982 children, we assessed serum lipids, body mass index and maximal oxygen consumption at baseline (2001-2003) and explored associations with respiratory health at follow-up (2007) using multiple logistic regression models. RESULTS: Lower levels of high-density lipoprotein cholesterol at age 11-12 years were found in subjects who reported ever asthma (58.2 vs. 60.0 mg/dL, P = 0.005) and active asthma (57.5 vs. 59.9 mg/dL, P = 0.010) in adolescence, in comparison with their respective reference groups. Total cholesterol, low-density lipoprotein and triglycerides had no association with any of the asthma outcomes. In contrast, with estimated odds ratios of 1.89 (95% CI 1.19-3.00) and 1.89 (95% CI 1.02-3.53), ever asthma and active asthma respectively appeared particularly pronounced among those who at baseline had high-density lipoprotein cholesterol <40 mg/dL, even after adjusting for potential confounders including body mass index and maximal oxygen consumption. CONCLUSIONS & CLINICAL RELEVANCE: Low-serum high-density lipoprotein cholesterol in childhood is associated with an increased risk for asthma in adolescence, suggesting a potential role of this lipoprotein in the pathogenesis of paediatric asthma.

The ribosomal S6 kinases, cAMP-responsive element-binding, and STAT3 proteins are regulated by different leukemia inhibitory factor signaling pathways in mouse embryonic stem cells.

Mouse embryonic stem (ES) cells remain "pluripotent" in vitro in the continuous presence of leukemia inhibitory factor (LIF). In the absence of LIF, ES cells are irreversibly committed to differentiate into various lineages. In this study we have set up an in vitro assay based on the anti-apoptotic activity of LIF to distinguish pluripotent from "differentiation-committed" ES cells. We have examined the phosphorylation profiles of known (STAT3 and ERKs) and identified new (ribosomal S6 kinases (RSKs) and cAMP-responsive element-binding protein (CREB)) LIF-regulated targets in ES and in ES-derived neuronal cells. We have demonstrated that although STAT3, a crucial player in the maintenance of ES cell pluripotency, is induced by LIF in all cell types tested, the LIF-dependent activation of RSKs is restricted to ES cells. We have shown that LIF-induced phosphorylation of RSKs in ES cells is dependent on ERKs, whereas STAT3 phosphorylation is not mediated by any known MAPK activities. Our results also demonstrate that the LIF-dependent phosphorylation of CREB is partially under the control of the RSK2 kinase.

Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome.

RSK2 is a growth factor-regulated serine-threonine protein kinase, acting in the Ras-Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Mutations in the RSK2 gene (RPS6KA3) on chromosome Xp22.2, have been found to cause Coffin-Lowry syndrome (CLS), an X-linked disorder characterized by psychomotor retardation, characteristic facial and digital abnormalities, and progressive skeletal deformations. By screening of 250 patients with clinical features suggestive of Coffin-Lowry syndrome, 71 distinct disease-associated RSK2 mutations have been identified in 86 unrelated families. Thirty-eight percent of mutations are missense mutations, 20% are nonsense mutations, 18% are splicing errors, and 21% are short deletion or insertion events. About 57% of mutations result in premature translation termination, and the vast majority are predicted to cause loss of function of the mutant allele. These changes are distributed throughout the RSK2 gene and show no obvious clustering or phenotypic association. However, some missense mutations are associated with milder phenotypes. In one family, one such mutation was associated solely with mild mental retardation. It is noteworthy that nine mutations were found in female probands, with no affected male relatives, ascertained through learning disability and mild but suggestive facial and digital dysmorphisms.

Activation of RSK by UV-light: phosphorylation dynamics and involvement of the MAPK pathway.

Ribosomal S6 kinases (RSKs) are serine/threonine kinases activated by mitogenic signals through the Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinases (MAPK/ERK). RSKs contain two heterologous complete protein kinase domains. Phosphorylation by ERK of the C-terminal kinase domain allows activation of the N-terminal kinase domain, which mediates substrate phosphorylation. In human, there are three isoforms of RSK (RSK1, RSK2, RSK3), whose functional specificity remains undefined. Importantly, we have shown that mutations in the RSK2 gene lead to the Coffin-Lowry syndrome (CLS). In this study, we characterize two monoclonal antibodies raised against phosphorylated forms of the N- and C-terminal domain of RSK2 (P-S227 and P-T577, respectively). Using these two antibodies, we show that stress signals, such as UV light, induce phosphorylation and activation of the three RSKs to an extent which is comparable to Epidermal Growth Factor (EGF)-mediated activation. The use of specific kinase inhibitors indicates that UV-induced phosphorylation and activation of RSK2 is mediated by the MAPK/ERK pathway, but that the Stress-Activated Protein Kinase 2 (SAPK2)/p38 pathway is also involved. These results modify the view of RSKs as kinases restricted to the mitogenic response and reveal a previously unappreciated role of MAPKs in stress induced signaling. Oncogene (2000) 19, 4221 - 4229