Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss.
Inactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in Apc(Min/+) mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from Apc(Min/+) mice. Taken together, these results indicate that cyclin D-CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC.
Cole
Alicia M
AM
Beatson Institute of Cancer Research, Glasgow, United Kingdom; School of Biosciences, Cardiff, United Kingdom.
Myant
Kevin
K
Reed
Karen R
KR
Ridgway
Rachel A
RA
Athineos
Dimitris
D
Van den Brink
Gijs R
GR
Muncan
Vanesa
V
Clevers
Hans
H
Clarke
Alan R
AR
Sicinski
Peter
P
Sansom
Owen J
OJ
D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D056742:Cyclin D2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D017353:Gene Deletion; D017491:Genes, APC; D016259:Genes, myc; D007150:Immunohistochemistry; D044483:Intestinal Polyposis / Q000235:genetics / Q000473:pathology; D051379:Mice; D008940:Mitotic Index; D016133:Polymerase Chain Reaction; D015854:Up-Regulation
D056742:Cyclin D2; D017931:DNA Primers; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6