Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc.
Inhibition of the mutationally activated Wnt cascade in colorectal cancer cell lines induces a rapid G1 arrest and subsequent differentiation. This arrest can be overcome by maintaining expression of a single Tcf4 target gene, the proto-oncogene c-Myc. Since colorectal cancer cells share many molecular characteristics with proliferative crypt progenitors, we have assessed the physiological role of c-Myc in adult crypts by conditional gene deletion. c-Myc-deficient crypts are lost within weeks and replaced by c-Myc-proficient crypts through a fission process of crypts that have escaped gene deletion. Although c-Myc(-/-) crypt cells remain in the cell cycle, they are on average much smaller than wild-type cells, cycle slower, and divide at a smaller cell size. c-Myc appears essential for crypt progenitor cells to provide the necessary biosynthetic capacity to successfully progress through the cell cycle.
Muncan
Vanesa
V
Hubrecht Laboratory, Nederlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Sansom
Owen J
OJ
Tertoolen
Leon
L
Phesse
Toby J
TJ
Begthel
Harry
H
Sancho
Elena
E
Cole
Alicia M
AM
Gregorieff
Alex
A
de Alboran
Ignacio Moreno
IM
Clevers
Hans
H
Clarke
Alan R
AR
D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000502:physiology; D018390:Gene Targeting; D016259:Genes, myc; D019426:Integrases / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008938:Mitosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins / Q000235:genetics*
D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; C045073:Cre recombinase; D019426:Integrases