The Growth Arrest and DNA Damage-inducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress. However, the pro-apoptotic activities have also positioned GADD45 as an essential player in oncogenesis. Emerging functional evidence implies that GADD45 proteins serve as tumor suppressors in response to diverse stimuli, connecting multiple cell signaling modules. Defects in the GADD45 pathway can be related to the initiation and progression of malignancies. Moreover, induction of GADD45 expression is an essential step for mediating anti-cancer activity of multiple chemotherapeutic drugs and the absence of GADD45 might abrogate their effects in cancer cells. In this review, we present a comprehensive discussion of the functions of GADD45 proteins, linking their regulation to effectors of cell cycle arrest, DNA repair and apoptosis. The ramifications regarding their roles as essential and central players in tumor growth suppression are also examined. We also extensively review recent literature to clarify how different chemotherapeutic drugs induce GADD45 gene expression and how its up-regulation and interaction with different molecular partners may benefit cancer chemotherapy and facilitate novel drug discovery.

Key Points• LIN28B regulates HbF expression in erythroblasts that are cultured from umbilical cord and adult human blood.• LIN28B expression manifested a more fetal-like phenotype among adult human erythroblasts.Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and b-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-toadult developmental transition. To explore the effects of LIN28B in human erythroid cell development, lentiviral transduction was used to knockdown LIN28B expression in erythroblasts cultured from human umbilical cord CD341 cells. The subsequent reduction in LIN28B expression caused increased expression of let-7 and significantly reduced HbF expression. Conversely, LIN28B overexpression in cultured adult erythroblasts reduced the expression of let-7 and significantly increased HbF expression. Cellular maturation was maintained including enucleation. LIN28B expression in adult erythroblasts increased the expression of g-globin, and the HbF content of the cells rose to levels >30% of their hemoglobin. Expression of carbonic anhydrase I, glucosaminyl (N-acetyl) transferase 2, and miR-96 (three additional genes marking the transition from fetal-toadult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of g-globin expression, was significantly down-regulated. Independent of LIN28B, experimental suppression of let-7 also reduced BCL11A expression and significantly increased HbF expression. LIN28B expression regulates HbF levels and causes adult human erythroblasts to differentiate with a more fetal-like phenotype. (Blood. 2013;122(6):1034-1041 IntroductionIn humans and some other mammals, the composition of hemoglobin tetramers in erythrocytes switch from fetal hemoglobin (HbF) (a2g2) to adult hemoglobin (HbA) (a2b2) during the last stages of fetal development until early infancy.1 HbF is the most important known modifier of the clinical symptoms for patients with sickle cell disease (SCD) and b-thalassemias, which are among the most common genetic disorders worldwide. 2,3 In patients with SCD, the polymerization of sickle hemoglobin results in erythrocyte deformation and hemolysis.4 SCD patient's clinical outcomes are largely improved by inhibition of the polymerization by HbF. 5 In b-thalassemias, decreased production of b-globin causes imbalanced globin polypeptide chain synthesis, and leads to severe effects on the erythroid cells' maturation and survival. The loss of b-globin expression may be compensated by an increase in HbF production that leads to improvement of the clinical phenotype. 6 The molecular mechanisms underlying the switch from HbF to HbA are still largely unknown. Genome-wide association studies (GWAS) in both normal individuals and patients with b-hemoglobinopathies have identified BCL11A, HSB1L-MYB, and HBB clusters as having an association with the persistence of Hb...

Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion, and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the NF-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by IGF1 in Axl knockdown cells restores Akt activity and proliferation. Taken together our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment.

Key Points The G9a methyltransferase inhibitor UNC0638 increased pancellular expression of HbF to levels greater than 30% in adult human erythroblasts. UNC0638 altered globin locus epigenetic status/protein occupancy favoring LCR interaction with fetal genes at the expense of adult genes.