TY - JOUR
T1 - Pten is essential for embryonic development and tumour suppression
AU - Di Cristofano, Antonio
AU - Pesce, Barbara
AU - Cordon-Cardo, Carlos
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We thank K. Podsypanina, P. Fisher and R. Parsons for useful discussion and for exchanging preliminary and unpublished data; K. Witty and K. Manova for the analysis of EBs features; M. Barna for help with the editing of the manuscript; J. H. Dong and W. Mark for help with the generation and the management of the Pten mutants; and J. Rosai for critical suggestions in the analysis of the pathological features of the mice. P.P.P. is a Scholar of the Leukemia Society of America. This work was supported by the Sloan-Kettering Institute (CA-08748).
PY - 1998
Y1 - 1998
N2 - The PTEN gene encodes a dual-specificity phosphatase mutated in a variety of human cancers. PTEN germline mutations are found in three related human autosomal dominant disorders, Cowden disease (CD), Lhermitte-Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the role of PTEN in ontogenesis and tumour suppression, we disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Pten(-/-) ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal and mesodermal derivatives. Pten(+/-) mice and chimaeric mice derived from Pten(+/-) ES cells showed hyperplastic-dysplastic changes in the prostate, skin and colon, which are characteristic of CD, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.
AB - The PTEN gene encodes a dual-specificity phosphatase mutated in a variety of human cancers. PTEN germline mutations are found in three related human autosomal dominant disorders, Cowden disease (CD), Lhermitte-Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the role of PTEN in ontogenesis and tumour suppression, we disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Pten(-/-) ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal and mesodermal derivatives. Pten(+/-) mice and chimaeric mice derived from Pten(+/-) ES cells showed hyperplastic-dysplastic changes in the prostate, skin and colon, which are characteristic of CD, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.
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U2 - 10.1038/1235
DO - 10.1038/1235
M3 - Article
C2 - 9697695
AN - SCOPUS:0031870959
SN - 1061-4036
VL - 19
SP - 348
EP - 355
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -
