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PMID:16311606

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Citation

Li, X, Luo, Y, Starremans, PG, McNamara, CA, Pei, Y and Zhou, J (2005) Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat. Cell Biol. 7:1202-12

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by progressive cyst formation and ultimate loss of renal function. Increased cell proliferation is a key feature of the disease. Here, we show that the ADPKD protein polycystin-2 (PC2) regulates the cell cycle through direct interaction with Id2, a member of the helix-loop-helix (HLH) protein family that is known to regulate cell proliferation and differentiation. Id2 expression suppresses the induction of a cyclin-dependent kinase inhibitor, p21, by either polycystin-1 (PC1) or PC2. The PC2-Id2 interaction is regulated by PC1-dependent phosphorylation of PC2. Enhanced Id2 nuclear localization is seen in human and mouse cystic kidneys. Inhibition of Id2 expression by RNA interference corrects the hyperproliferative phenotype of PC1 mutant cells. We propose that Id2 has a crucial role in cell-cycle regulation that is mediated by PC1 and PC2.

Links

PubMed Online version:10.1038/ncb1326

Keywords

Active Transport, Cell Nucleus; Animals; Cell Cycle; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21/antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21/genetics; Gene Expression Regulation; Humans; Inhibitor of Differentiation Protein 2/genetics; Inhibitor of Differentiation Protein 2/metabolism; Kidney/chemistry; Membrane Proteins/analysis; Membrane Proteins/metabolism; Membrane Proteins/physiology; Mice; Phosphorylation; Proteins/analysis; Proteins/physiology; TRPP Cation Channels/analysis

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PKD1

located_in

GO:0005737: cytoplasm

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TFE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P41136

F

Seeded From UniProt

complete

MOUSE:ID2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15806-2

F

Seeded From UniProt

complete

HUMAN:PKD1

involved_in

GO:0045737: positive regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ID2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13563

F

Seeded From UniProt

complete

HUMAN:ID2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ID2

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ID2

enables

GO:0044325: transmembrane transporter binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13563

F

Seeded From UniProt

complete

HUMAN:PKD2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q02363

F

Seeded From UniProt

complete

HUMAN:PKD2

located_in

GO:0005737: cytoplasm

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PKD2

enables

GO:0043398: HLH domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q02363

F

Seeded From UniProt

complete

HUMAN:PKD2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PKD2

involved_in

GO:0045737: positive regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PKD2

involved_in

GO:0042994: cytoplasmic sequestering of transcription factor

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PKD2

involved_in

GO:2000134: negative regulation of G1/S transition of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PKD1

involved_in

GO:2000045: regulation of G1/S transition of mitotic cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PKD1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PKD1

involved_in

GO:0045737: positive regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

part_of:(GO:2000045)

Seeded From UniProt

complete

MOUSE:PKD1

part_of

GO:0005737: cytoplasm

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PKD1

involved_in

GO:0032092: positive regulation of protein binding

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PKD1

involved_in

GO:0042994: cytoplasmic sequestering of transcription factor

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ID2

colocalizes_with

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ID2

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ID2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ID2

enables

GO:0044325: ion channel binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13563

F

Seeded From UniProt

complete

HUMAN:ID2

involved_in

GO:2000045: regulation of G1/S transition of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ID2

involved_in

GO:0071931: positive regulation of transcription involved in G1/S transition of mitotic cell cycle

ECO:0000305: curator inference used in manual assertion

GO:2000045

P

Seeded From UniProt

complete


See also

References

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