Cell Cycle-regulated Phosphorylation of Hamartin, the Product of the Tuberous Sclerosis Complex 1 Gene, by Cyclin-dependent Kinase 1/Cyclin B

Aristotelis Astreinidis, William Senapedis, Thomas R. Coleman, Elizabeth Petri Henske

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Tuberous sclerosis complex is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, and benign tumors of the brain, skin, heart, and kidneys. Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin. Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle. In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (Thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex. These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle.

Original languageEnglish (US)
Pages (from-to)51372-51379
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number51
DOIs
StatePublished - Dec 19 2003
Externally publishedYes

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CDC2 Protein Kinase
Cyclin B
Phosphorylation
Tuberous Sclerosis
Cell Cycle
Genes
Cells
G2 Phase
Cell Division
Tumors
Nocodazole
Tuberous Sclerosis 1
tuberous sclerosis complex 1 protein
Sirolimus
Threonine
Tumor Suppressor Genes
Brain Neoplasms
Intellectual Disability
Alanine
tuberous sclerosis complex 2 protein

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cell Cycle-regulated Phosphorylation of Hamartin, the Product of the Tuberous Sclerosis Complex 1 Gene, by Cyclin-dependent Kinase 1/Cyclin B. / Astreinidis, Aristotelis; Senapedis, William; Coleman, Thomas R.; Henske, Elizabeth Petri.

In: Journal of Biological Chemistry, Vol. 278, No. 51, 19.12.2003, p. 51372-51379.

Research output: Contribution to journalArticle

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