C/EBPalpha is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells.
In this report, we present novel findings that implicate CCAAT/enhancer-binding protein (C/EBPalpha) in regulating the expression and activity of calpain 3 in vivo and data showing a new physiological substrate for calpain 3, cyclin A. Our results demonstrate that cleavage of cyclin A by calpain 3 occurs in mouse and human myeloid precursor cells. Calpain 3 cleaves cyclin A in vitro and in vivo, resulting in the production of a truncated product that lacks the N-terminal destruction box required for its degradation at the end of mitosis. The cleaved form of cyclin A retains the cyclin-dependent kinase (cdk) binding domain and forms active complexes with cdk2. Calpain 3-mediated cleavage of cyclin A is lacking in C/EBPalpha-/- mice, which are not able to produce mature granulocytes. Our data support a model in which calpain 3-mediated cleavage of cyclin A in dividing myeloid progenitor cells is important for the onset of differentiation. Deficits in this pathway in C/EBPalpha-/- mice might contribute to the failure of these mice to produce mature granulocytes. These data reveal a new pathway involving tightly controlled post-translational processing of cyclin A during differentiation of granulocytes.
Welm
Alana L
AL
Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Timchenko
Nikolai A
NA
Ono
Yasuko
Y
Sorimachi
Hiroyuki
H
Radomska
Hannah S
HS
Tenen
Daniel G
DG
Lekstrom-Himes
Julie
J
Darlington
Gretchen J
GJ
D000818:Animals; D000831:Animals, Newborn; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology*; D002154:Calpain / Q000502:physiology*; D019925:Cyclin A / Q000737:chemistry / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity
D022763:CCAAT-Enhancer-Binding Protein-alpha; D019925:Cyclin A; D002154:Calpain