Cyclin-dependent kinase-mediated phosphorylation plays a critical role in the oncogenic functions of PELP1.
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 Ser(477) and Ser(991) of PELP1 as CDK phosphorylation sites. Using the PELP1 Ser(991) 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.
Nair
Binoj C
BC
Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7836, San Antonio, TX 78229-3900, USA.
Nair
Sujit S
SS
Chakravarty
Dimple
D
Challa
Rambabu
R
Manavathi
Bramanandam
B
Yew
P Renee
PR
Kumar
Rakesh
R
Tekmal
Rajeshwar Rao
RR
Vadlamudi
Ratna K
RK
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
D056970:Co-Repressor Proteins; D050684:E2F Transcription Factors; C438485:PELP1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases
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