Suppressors of cytokine signaling (SOCS) are important mediators of this type of interaction, as their

expression is induced by cytokines and their function is to act in a negative feedback loop to inhibit signaling through a whole host of receptors, including those of insulin and several growth factors.41 Specifically in hepatocytes, SOCS3 is highly induced after PH,42 is critical to shutting down cytokine signaling after PH and hepatocytes without SOCS3 were hyper-proliferative in response to growth factors in culture.43 Mice without SOCS3 in hepatocytes demonstrated enhanced regeneration after PH, and an earlier development of HCC after DEN injection, suggesting

that this protein is critical in controlling normal and abnormal proliferative responses in the Selleck SCH727965 liver. Given the simultaneous activation of multiple diverse pathways that occurs after PH, one might expect significant changes in global gene expression during this process. In evaluating gene expression profiles during early G1, late G1, and the S phase of the cell cycle after PH, Greenbaum and colleagues described an initial decrease in the expression of genes involved in steroid and lipid metabolism and hormone biosynthesis, i.e. normal activities of the quiescent liver.44 As expected, later in G1 genes involved in protein MCE公司 synthesis and cytoskeletal organization were up-regulated, a LEE011 pattern which continued through S phase, when expression of nucleotide metabolism genes became more prominent. Gene expression profiling was recently used to examine the differential proliferative response that occurs after 1/3 (minimal proliferation) versus

2/3 PH (robust proliferation). It was found that even 1/3 PH leads to significant changes in gene expression.45 Interestingly though, between 4 and 12 h after the two operations, a transcriptional shift seemed to occur, committing hepatocytes toward replication. This transcriptional shift consisted of the activation of genes enriched in transcription regulatory elements for FOXD3, FOXI1, CUX1, ER and E2F-1 at 4 h after 2/3 PH, and their replacement at 12 h by genes enriched in TREs for c-jun, CCAAT box, Myb, Ets-1, Elk-1 and USF, which are associated with DNA replication. These data demonstrate that the liver initially responds to PH with massive changes in gene expression, even if the operation does not result in DNA replication, and suggest that genomic and epigenomic changes function as a “wake up” call for quiescent hepatocytes to prepare them for the decision to replicate, which occurs 12 h after PH or later. Micro RNAs appear to serve as an additional layer of regulation during liver regeneration.