The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex

Aristotelis Astreinidis, Jiyoon Kim, Crystal M. Kelly, Beatrix A. Olofsson, Behzad Torabi, Elena M. Sorokina, Jane Azizkhan-Clifford

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Specificity protein 1 (SP1) is an essential transcription factor implicated in the regulation of genes that control multiple cellular processes, including cell cycle, apoptosis, and DNA damage. Very few nontranscriptional roles for SP1 have been reported thus far. Using confocal microscopy and centrosome fractionation, we identified SP1 as a centrosomal protein. Sp1-deficient mouse embryonic fibroblasts and cells depleted of SP1 by RNAi have increased centrosome number associated with centriole splitting, decreased microtubule nucleation, chromosome misalignment, formation of multipolar mitotic spindles and micronuclei, and increased incidence of aneuploidy. Using mass spectrometry, we identified P70S6K, an effector of the mTOR/raptor (mTORC1) kinase complex, as a novel interacting protein of SP1. We found that SP1-deficient cells have increased phosphorylation of the P70S6K effector ribosomal protein S6, suggesting that SP1 participates in the regulation of the mTORC1/P70S6K/S6 signaling pathway. We previously reported that aberrant mTORC1 activation leads to supernumerary centrosomes, a phenotype rescued by the mTORC1 inhibitor rapamycin. Similarly, treatment with rapamycin rescued the multiple centrosome phenotype of SP1-deficient cells. Taken together, these data strongly support the hypothesis that SP1 is involved in the control of centrosome number via regulation of the mTORC1 pathway, and predict that loss of SP1 function can lead to aberrant centriole splitting, deregulated mTORC1 signaling, and aneuploidy, thereby contributing to malignant transformation.

Original languageEnglish (US)
Pages (from-to)282-297
Number of pages16
JournalGenes Chromosomes and Cancer
Volume49
Issue number3
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

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Raptors
Sp1 Transcription Factor
Centrioles
Chromosomal Instability
Sirolimus
Centrosome
Proteins
70-kDa Ribosomal Protein S6 Kinases
Aneuploidy
Ribosomal Protein S6
Phenotype
S 6
Spindle Apparatus
RNA Interference
Confocal Microscopy
Microtubules
DNA Damage
mechanistic target of rapamycin complex 1

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cancer Research

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The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex. / Astreinidis, Aristotelis; Kim, Jiyoon; Kelly, Crystal M.; Olofsson, Beatrix A.; Torabi, Behzad; Sorokina, Elena M.; Azizkhan-Clifford, Jane.

In: Genes Chromosomes and Cancer, Vol. 49, No. 3, 01.03.2010, p. 282-297.

Research output: Contribution to journalArticle

Astreinidis, Aristotelis ; Kim, Jiyoon ; Kelly, Crystal M. ; Olofsson, Beatrix A. ; Torabi, Behzad ; Sorokina, Elena M. ; Azizkhan-Clifford, Jane. / The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex. In: Genes Chromosomes and Cancer. 2010 ; Vol. 49, No. 3. pp. 282-297.
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