ABSTRACT
Eukaryotic translation initiation factor 4E was recently shown to be a substrate of mTORC1, suggesting it may be a mediator of mTORC1 signaling. Here, we present evidence that eIF4E phosphorylated at S209 interacts with TOS motif of S6 Kinase1 (S6K1). We also show that this interaction is sufficient to overcome rapamycin sensitivity and mTORC1 dependence of S6K1. Furthermore, we show that eIF4E-TOS interaction relieves S6K1 from auto-inhibition due to carboxy terminal domain (CTD) and primes it for hydrophobic motif (HM) phosphorylation and activation in mTORC1 independent manner. We conclude that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif to influence its state of HM phosphorylation and inducing its activation.
Subject(s)
Eukaryotic Initiation Factor-4E/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Ribosomal Protein S6 Kinases/chemistry , Ribosomal Protein S6 Kinases/metabolism , Amino Acid Motifs , Animals , Cell Line, Tumor , Enzyme Activation/drug effects , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Models, Biological , NIH 3T3 Cells , Phosphorylation/drug effects , Protein Binding/drug effects , Protein Serine-Threonine Kinases/metabolism , Sirolimus/pharmacologyABSTRACT
Human papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection and is one of the causal factors in cervical cancer. Understanding the epidemiology of this infection is an important step toward developing strategies for its prevention. Cervical samples from 210 healthy women with normal and abnormal cytomorphology were studied for the detection of HPV DNA by polymerase chain reaction (PCR), utilizing the two most commonly used consensus primer sets. The primers; MY09/MY11 and GP5+/GP6+ located within the L1 region of HPV genome, amplified a broad spectrum of HPV genotypes in a single reaction. The PCR amplification of HPV genomes is a sensitive method that is used for the detection of cervicovaginal HPV. With the aim of identifying the HPV types, samples were also subjected to PCR using specific primers for HPV types 16 and 18. In addition, basic demographic information, sociodemographic characteristics, and sexual behavior were recorded. HPV was detected in 13.8% of the study population aged 18 to 57 years using PCR. HPV16 (6.6%) was more commonly detected than HPV18 (3.8%). The highest prevalence of HPV infection was seen in women below 27 years old, and then, a new increase was seen higher than the age of 48. In conclusion, our study demonstrated that younger age at marriage, economic status, parity, and dwelling are the major risk factors determining HPV infection.
