title: Heregulin, a new regulator of telomere length in human cells.
abstract: The growth factor heregulin (HRG) promotes breast cancer (BC) tumorigenesis and metastasis and differentially modulates BC cell responses to DNA-damaging agents via its dual extracellular and nuclear localization. Given the central role of telomere dysfunction to drive carcinogenesis and to alter the chemotherapeutic profile of transformed cells, we hypothesized that an unanticipated nuclear function of HRG might be to regulate telomere length. Engineered overexpression of the HRGβ2 isoform in non-aggressive, HRG-negative MCF-7 BC cells resulted in a significant shortening of telomeres (up to 1.3 kb) as measured by Southern blotting of telomere terminal restriction fragments. Conversely, antisense-mediated suppression of HRGβ2 in highly aggressive, HRG-overexpressing MDA-MB-231 and Hs578T cells increased telomere length up to 3.0 kb. HRGβ2 overexpression promoted a marked upregulation of telomere-binding protein 2 (TRF2) protein expression, whereas its knockdown profoundly decreased TRF2 expression. Double staining of endogenous HRGβ2 with telomere-specific peptide nucleic acid probe/fluorescence in situ hybridization (PNA/FISH) revealed the partial localization of HRG at the chromosome ends. Moreover, a predominantly nucleoplasmic staining pattern of endogenous HRGβ2 appeared to co-localize with TRF2 and, concomitantly with RAP1, a telomere regulator that specifically interacts with TRF2. Small interfering RNA-mediated knockdown of HRG decreased the expression of TRF2 and RAP1, decreased their presence at chromosome ends, and coincidentally resulted in the formation of longer telomeres. This study uncovers a new function for HRGβ2 in controlling telomere length, in part due to its ability to regulate and interact with the telomere-associated proteins TRF2 and RAP1.
authors: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology (ICO), Girona, Spain.|Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors: Javier A
authors: JA
authors: Menendez
authors: Laboratory of Hematology Service, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Miguel A
authors: MA
authors: Rubio
authors: Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA, USA.|Buck Institute for Research on Aging, Novato, CA, USA.
authors: Judith
authors: J
authors: Campisi
authors: Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA.|Mayo Clinic Cancer Center, Rochester, MN, USA.
authors: Ruth
authors: R
authors: Lupu
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*; D059506:Telomere Shortening / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D020890:Neuregulin-1; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C087230:heregulin beta1
keywords: RAP1; TRF2; aging; cancer; heregulin; telomere