Cyclin-dependent kinase-mediated phosphorylation plays a critical role in the oncogenic functions of PELP1

Binoj C. Nair, Sujit S. Nair, Dimple Chakravarty, Rambabu Challa, Bramanandam Manavathi, P. Renee Yew, Rakesh Kumar, Rajeshwar Rao Tekmal, Ratna K. Vadlamudi

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Estrogen receptor (ER) signaling plays an important role in breast cancer progression, and ER functions are influenced by coregulatory proteins. PELP1 (proline-, glutamic acid-, and leucine-rich protein 1) is a nuclear receptor coregulator that plays an important role in ER signaling. Its expression is deregulated in hormonal cancers. We identified PELP1 as a novel cyclin-dependent kinase (CDK) substrate. Using site-directed mutagenesis and in vitro kinase assays, we identified Ser477 and Ser991 of PELP1 as CDK phosphorylation sites. Using the PELP1 Ser991 phospho-specific antibody, we show that PELP1 is hyperphosphorylated during cell cycle progression. Model cells stably expressing the PELP1 mutant that lack CDK sites had defects in estradiol (E2)-mediated cell cycle progression and significantly affected PELP1-mediated oncogenic functions in vivo. Mechanistic studies showed that PELP1 modulates transcription factor E2F1 transactivation functions, that PELP1 is recruited to pRb/E2F target genes, and that PELP1 facilitates ER signaling cross talk with cell cycle machinery. We conclude that PELP1 is a novel substrate of interphase CDKs and that its phosphorylation is important for the proper function of PELP1 in modulating hormone-driven cell cycle progression and also for optimal E2F transactivation function. Because the expression of both PELP1 and CDKs is deregulated in breast tumors, CDK-PELP1 interactions will have implications in breast cancer progression.

Original languageEnglish (US)
Pages (from-to)7166-7175
Number of pages10
JournalCancer Research
Volume70
Issue number18
DOIs
StatePublished - Sep 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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