ABSTRACT
Caveolae are plasma membrane regions enriched in Caveolin proteins which regulate vesicular transport, endocytosis, and cell signaling. IGF-I receptor (IGF-IR) localizes in caveolae and tyrosine phosphorylates Caveolin-1 (Cav-1), the most represented caveolar protein. Cav-1 participates to IGF-IR internalization and signaling directly interacting with IGF-IR and its substrates. Recently, polymerase I and transcript release factor (PTRF) or Cavin-1, has been identified in the caveolar backbone. PTRF does not play a Cav-1 ancillary role and emerging data support a direct role of PTRF in IGF-IR signaling. PTRF and Cav-1 can bind IGF-IR and regulate IGF-IR internalization and plasma membrane replacement, mechanisms frequently deregulated in cancer cells. Although the exact roles of Cav-1 and IGF-IR in human cancer continue to be a matter of some debate, there is a strong evidence for an association between Cav-1 and IGF-IR in cancer development. With the discovery of IGF-IR interaction with PTRF in caveolae, new insight emerged to understand the growing functions of these domains in IGF-I action.
Subject(s)
Caveolin 1/physiology , RNA-Binding Proteins/physiology , Receptor, IGF Type 1/metabolism , Animals , Caveolin 1/genetics , Caveolin 1/metabolism , Endocytosis/genetics , Endocytosis/physiology , Gene Expression Regulation, Neoplastic , Humans , Neoplasms/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Receptor, IGF Type 1/genetics , Signal Transduction/genetics , Signal Transduction/physiologyABSTRACT
RNA polymerase (RNAP) currently represents an important target for the development of new antibacterial agents. RNAP is a nucleotidyl transferase enzyme able to generate an RNA copy of a DNA or RNA template chain, controlling initiation and termination of transcription. RNAP is found in nature in all eukaryotes, prokaryotes and archaea, as well as in many viruses. Bacterial RNAP is a large molecule (about 400 kDa) and its core structure is composed of four polypeptide subunits: alpha (alpha) required for assembly of the enzyme, beta (beta) involved in chain initiation and elongation, beta' (beta') which binds to the DNA template, and omega (omega) which constrains the beta' subunit and aids its assembly into RNAP, in the stoichiometry alpha2betabeta'omega. The bacterial enzyme differs both from eukaryotic RNAP, which is composed of different subunits and is present in several variants, and from archaeal or viral RNAP. These differences allow to selectively target the bacterial enzyme with appropriately designed inhibitors, excluding interactions with eukaryotic RNAP, accounting for the deep interest developed around these compounds as selective antibacterial agents. In this review the known natural and synthetic inhibitors of RNAP will be described considering their mechanism of action, biological activity, availability of analogues, Structure Activity Relationship (SAR) information and clinical use when already approved or recently entered into clinical trials.
