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PMID:18339895

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Citation

Waning, DL, Li, B, Jia, N, Naaldijk, Y, Goebel, WS, HogenEsch, H and Chun, KT (2008) Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis. Blood 112:320-9

Abstract

In vitro studies indicate that Cul4A ubiquitin ligases target for ubiquitin-mediated proteolysis regulators of cell-cycle progression, apoptosis, development, and DNA repair. In hematopoietic cell lines, studies by our group and others showed that Cul4A ligases regulate proliferation and differentiation in maturing myeloid and erythroid cells. In vivo, Cul4A-deficient embryos die in utero. Cul4A haploinsufficient mice are viable but have fewer erythroid and primitive myeloid progenitors. Yet, little more is known about Cul4A function in vivo. To examine Cul4A function in adults, we generated mice with interferon-inducible deletion of Cul4A. Cul4A deficiency resulted in DNA damage and apoptosis of rapidly dividing cells, and mutant mice died within 3 to 10 days after induction with dramatic atrophy of the intestinal villi, bone marrow, and spleen, and with hematopoietic failure. Cul4A deletion in vivo specifically increased cellular levels of the Cul4A ligase targets Cdt1 and p27(Kip1) but not other known targets. Bone marrow transplantation studies with Cul4A deletion in engrafted cells specifically isolated analysis of Cul4A function to hematopoietic cells and resulted in hematopoietic failure. These recipients died within 9 to 11 days, demonstrating that in hematopoietic cells, Cul4A is essential for survival.

Links

PubMed PMC2442743 Online version:10.1182/blood-2007-11-126300

Keywords

Animals; Apoptosis; Cell Cycle Proteins/analysis; Cell Survival; Cullin Proteins/genetics; Cullin Proteins/physiology; Cyclin-Dependent Kinase Inhibitor p27/analysis; DNA-Binding Proteins/analysis; Hematopoiesis; Hematopoietic System/cytology; Mice; Mice, Knockout

Significance

Annotations

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

CAEEL:CUL4

incorrect (CACAO)

GO:0006275: regulation of DNA replication

ECO:0000304:

P

intro “Cul4 is important for regulating DNA replication” Discussion (pg:326) without the CUL-4 cullin… multiple rounds of DNA replication were initiated in a single cell cycle,

complete

CAEEL:CUL4

incorrect (CACAO)

GO:0048589 : developmental growth

ECO:0000304:

P

Discussion (pg:326) without the CUL-4 cullin...development arrested at the L2 larval stage..

complete

MOUSE:CUL4A

incorrect (CACAO)

GO:0045995 : regulation of embryonic development

ECO:0000304:

P

intro “...mutant embryos did not survive….”

complete

MOUSE:CUL4A

GO:0002244 : hemopoietic progenitor cell differentiation

ECO:0000315:

P

Figure 3, table 1

complete

MOUSE:CUL4A

GO:0051246 : regulation of protein metabolic process

ECO:0000315:

P

figure 5

complete

MOUSE:CUL4A

acts_upstream_of_or_within

GO:0030097: hemopoiesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3805522

P

Seeded From UniProt

complete


See also

References

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