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PMID:18305152

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Citation

Ayala, YM, Misteli, T and Baralle, FE (2008) TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. Proc. Natl. Acad. Sci. U.S.A. 105:3785-9

Abstract

TDP-43 (for TAR DNA binding protein) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in specific pre-mRNA splicing and transcription events. TDP-43 recently has been identified as the main component of cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), two neurodegenerative disorders. The cellular role of this protein remains to be identified. Here, we show that loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis. Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. The control of Cdk6 expression mediated by TDP-43 involves GT repeats in the target gene sequence. Cdk6 up-regulation in TDP-43-depleted cells is accompanied by an increase in phosphorylation of two of its major targets, the retinoblastoma protein pRb and pRb-related protein pRb2/p130. TDP-43 silencing also is followed by changes in the expression levels of several factors that control cell proliferation. Morphological nuclear defects and increased apoptosis upon TDP-43 loss are mediated via the pRb pathway because pRb-negative cells (Saos-2) do not undergo programmed cell death or nuclear shape deformation upon TDP-43 removal. Our results identify a regulatory target of TDP-43 and show that TDP-43 depletion has important consequences in essential metabolic processes in human cells.

Links

PubMed PMC2268791 Online version:10.1073/pnas.0800546105

Keywords

Animals; Apoptosis; Chickens; Conserved Sequence; Cyclin-Dependent Kinase 6/chemistry; Cyclin-Dependent Kinase 6/genetics; Cyclin-Dependent Kinase 6/metabolism; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Down-Regulation/genetics; HeLa Cells; Humans; Nuclear Envelope/metabolism; Oligonucleotide Array Sequence Analysis; Phosphorylation; RNA, Messenger/genetics; RNA, Messenger/metabolism; Repetitive Sequences, Amino Acid; Repressor Proteins/metabolism; Retinoblastoma Protein/metabolism; Retinoblastoma-Like Protein p130/metabolism; Up-Regulation/genetics

Significance

Annotations

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

HUMAN:TADBP

GO:0071765: nuclear inner membrane organization

ECO:0000315:

P

Figure 4 - "The lack of TDP-43 led to an uneven distribution of the nuclear envelope protein emerin along the membrane, with discrete regions of either protein accumulation or lack of protein" This proves that TDP-30 is involved in the organization of the nuclear inner membrane. With the depletion of TDP-30 the proteins that make up the inner membrane of the nucleus began to be disorganized all across the membrane.

complete
CACAO 7485

HUMAN:TADBP

GO:0042981: regulation of apoptotic process

ECO:0000315:

P

Figure 4 - "U2OS showed an increase in TUNEL staining and nuclear fragmentation upon TDP-43 depletion" Part B in the figure shows that with the depletion of TDP-43 nuclear fragmentation involved in apoptosis began. The samples used were also positive for enzymes consistant with programmed cell death.

complete
CACAO 7490

HUMAN:TADBP

GO:0051726: regulation of cell cycle

ECO:0000315:

P

Figure 3 - "U2OS cells showed an alteration of the cell cycle pattern after removal of TDP-43 (Fig. 3B) resulting in a 60% decrease of cells in G0/G1 accompanied by a corresponding increase in S and G2/M cells." This proves that TDP-43 regulates the distribution of the cell cycle phases.

complete
CACAO 7497

HUMAN:TADBP

GO:0001933: negative regulation of protein phosphorylation

ECO:0000315:

P

Figure 3 - shows that when TDP-43 was silenced there was an increase in the phosphorylation of pRb and p130

complete
CACAO 7502

HUMAN:TADBP

GO:0010629: negative regulation of gene expression

ECO:0000315:

P

Figure 2 shows that depletion of TDP-43 led to the up-regulation of Cyclin-Dependent Protein Kinase 6 proving that TDP-43 negatively regulates the gene expression of CDK6.

complete
CACAO 7513

HUMAN:TADBP

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TADBP

involved_in

GO:0001933: negative regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TADBP

involved_in

GO:0051726: regulation of cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TADBP

involved_in

GO:0042981: regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TADBP

involved_in

GO:0071765: nuclear inner membrane organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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