Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells

Blood. 2003 Jul 1;102(1):254-61. doi: 10.1182/blood-2002-10-3149. Epub 2003 Mar 13.

Abstract

All-trans retinoic acid (ATRA)-induced growth arrest of myeloid cells is associated with a sequential regulation of cyclins and cyclin-dependent kinase inhibitors (CKIs), which modulates the cell cycle machinery and inhibits the G1-S phase progression. ATRA treatment of myeloid cells induces up-regulation and tyrosine phosphorylation of Stat1, a member of the STAT (signal transducer and activator of transcription) transcription factor family that has been implicated in growth arrest in response to interferons. We have previously shown that ATRA-induced cell cycle arrest is dependent on tyrosinephosphorylated Stat1. In this study, we show that there is a basal level of Stat1 Ser727 phosphorylation in U-937 cells, which is transiently increased in response to ATRA treatment. Using Stat1Ser727Ala-expressing sublines, we provide evidence that Ser727 phosphorylation of Stat1 is required for ATRA-induced growth arrest. To shed further light on the role of Stat1 in ATRA-induced cell cycle arrest, cyclin and CKI expression was analyzed during ATRA treatment in U-937 sublines expressing Stat1Ser727Ala and Stat1Tyr701Phe. Our results show that Ser727/Tyr701-phosphorylated Stat1 plays a key role as a prerequisite for the ATRA-induced down-regulation of c-Myc; cyclins A, B, D2, D3, and E; and the simultaneous up-regulation of p27Kip1, associated with arrest in the G0/G1 phase of the cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation*
  • Humans
  • Interphase / drug effects
  • Interphase / physiology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA, Messenger / analysis
  • STAT1 Transcription Factor
  • Serine / metabolism
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology*
  • Tretinoin / pharmacology*
  • Tumor Suppressor Proteins / genetics
  • Tyrosine / metabolism
  • U937 Cells

Substances

  • Cell Cycle Proteins
  • Cyclins
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Tyrosine
  • Serine
  • Tretinoin