The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.
Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.
Karuman
P
P
Department of Cell Biology, Harvard Medical School, 02115, Boston, MA, USA.
Gozani
O
O
Odze
R D
RD
Zhou
X C
XC
Zhu
H
H
Shaw
R
R
Brien
T P
TP
Bozzuto
C D
CD
Ooi
D
D
Cantley
L C
LC
Yuan
J
J
D000091162:AMP-Activated Protein Kinase Kinases; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases