Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer.
Because colorectal cancers (CRCs) frequently display APC mutation, inhibition of apoptosis, and increased expression of the antiapoptotic protein survivin, we hypothesized that APC mutation inhibits apoptosis by allowing constitutive survivin expression. Using HT-29 CRC cell lines having inducible wild-type APC (wt-APC) or transfected dominant-negative TCF-4, we show that wt-APC down-regulates survivin expression via APC/beta-catenin/TCF-4 signaling. Using normal colonic epithelium, we found survivin by immunostaining/reverse transcription-PCR to be preferentially expressed in the lower crypt (which inversely correlates with wt-APC's expression pattern). Thus, wt-APC, by progressively decreasing survivin and increasing apoptosis from crypt bottom to top, may limit the population size of stem cells and other proliferative cells in the lower crypt; mutant APC may allow expansion of these populations, thereby initiating tumorigenesis.
Zhang
T
T
Division of Genetic and Preventive Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Otevrel
T
T
Gao
Z
Z
Gao
Z
Z
Ehrlich
S M
SM
Fields
J Z
JZ
Boman
B M
BM
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D003106:Colon / Q000378:metabolism* / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology*; D005786:Gene Expression Regulation / Q000502:physiology; D019073:HT29 Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000077022:Survivin; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection
D025601:Adenomatous Polyposis Coli Protein; C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors