title: hnRNP K binds a core polypyrimidine element in the eukaryotic translation initiation factor 4E (eIF4E) promoter, and its regulation of eIF4E contributes to neoplastic transformation.
abstract: Translation initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a key role in regulation of cellular proliferation. Its effects on the m7GpppN mRNA cap are critical because overexpression of eIF4E transforms cells, and eIF4E function is rate-limiting for G1 passage. Although we identified eIF4E as a c-Myc target, little else is known about its transcriptional regulation. Previously, we described an element at position -25 (TTACCCCCCCTT) that was critical for eIF4E promoter function. Here we report that this sequence (named 4EBE, for eIF4E basal element) functions as a basal promoter element that binds hnRNP K. The 4EBE is sufficient to replace TATA sequences in a heterologous reporter construct. Interactions between 4EBE and upstream activator sites are position, distance, and sequence dependent. Using DNA affinity chromatography, we identified hnRNP K as a 4EBE-binding protein. Chromatin immunoprecipitation, siRNA interference, and hnRNP K overexpression demonstrate that hnRNP K can regulate eIF4E mRNA. Moreover, hnRNP K increased translation initiation, increased cell division, and promoted neoplastic transformation in an eIF4E-dependent manner. hnRNP K binds the TATA-binding protein, explaining how the 4EBE might replace TATA in the eIF4E promoter. hnRNP K is an unusually diverse regulator of multiple steps in growth regulation because it also directly regulates c-myc transcription, mRNA export, splicing, and translation initiation.
authors: Cancer Research Center at Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA.
authors: Mary
authors: M
authors: Lynch
authors: Li
authors: L
authors: Chen
authors: Michael J
authors: MJ
authors: Ravitz
authors: Sapna
authors: S
authors: Mehtani
authors: Kevin
authors: K
authors: Korenblat
authors: Michael J
authors: MJ
authors: Pazin
authors: Emmett V
authors: EV
authors: Schmidt
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006367:HeLa Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051381:Rats; D016385:TATA Box / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D034641:Heterogeneous-Nuclear Ribonucleoprotein K