PTEN is a tumor suppressor highly mutated in a variety of human cancers. We found that Pten inactivation in the mouse results in early embryonic lethality and that Pten can act as a bona fide tumor suppressor in vivo. We have also shown that concomitant Pten and p27 losses are critical events in cooperative oncogenesis and demonstrated that Pten is haploinsufficient in some of its biological functions. We hypothesize that Pten is also haploinsufficient for tumor suppression and that its inactivation perturbs key developmental programs. We will test this hypothesis and study the molecular mechanisms by which PTEN suppresses tumorigenesis through a direct genetic approach with the following Specific Aims: 1. To define, in conditional Pten mice, the role of Pten in ontogenesis and tumorigenesis. We have generated Pten/floxed mice which we will utilize to conditionally inactivate Pten in: i) the developing limb given the fact germ line PTEN mutations in humans have been associated with bilateral hand malformations; ii) the hemopoietic mesoderm; and iii) in Pten null mosaic mutant embryos, an approach which has allowed us to delay and in some cases circumvent embryonic lethality. Ontogenesis and tumorigenesis will be studied in these conditional mutants, 2, To assess genetically the consequence and relevance of Pten haploinsufficieney in tumorigenesis in various tissues. We have generated compound mutants (Pten Hy/-) in which the expression of Pten is further reduced as compared to Pten +/- mutants (Pten hypomorph mutants). These mice are viable and preliminary results indicate that tumorigenesis is accelerated in these mutants. We will assess whether and in which tissue complete or partial Pten inactivation is required for tumorigenesis and metastasization. 3. To determine in conditional inducible mutants the consequence of Pten inactivation throughout aging. Aging and telomere shortening have a dramatic impact on tumor type, onset and incidence. We will utilize conditional inducible Pten mutants (Pten/in) in which the gene can be disrupted employing a tetracycline (Tet) regulated system, to inactivate Pten at various times during the mouse life span. Furthermore, Pten /in will be crossed with rnTer """"""""1""""""""(for telomere shortening), p66 she (mice whose life span is markedly prolonged) or TTD _m (mice with premature aging) mutants. Tumorigenesis and metastasization will be studied in these mutants. 4. To determine the basis of the functional cross talk between PTEN and p27 KiP in tumor suppression: the role of Skp2. We find that Pten inactivation results in increased expression of the F-box protein Skp2 and, in turn, in p27 Kwdegradation, but does not affect p27 KIPlocalization. We will dissect the molecular basis of the Pten/Akt/Skp2/p27 KxP cross talk and assess the genetic relevance of Skp2 in Pten inactivation-driven tumorigenesis. To this end, Pten +/- mutants will be intercrossed with Skp2 transgenic and KO mice to determine whether overexpression or inactivation of Skp2 cooperates or blocks tumorigenesis caused by Pten inactivation. We will also determine whether concomitant Skp2 inactivation rescues the early embryonic lethality observed in Pten /"""""""" mutants. 5. To determine the molecular mechanisms of growth suppression by PTEN through cell-cycle arrest. PTEN can suppress cell growth (Gl-arrest) independently of its phosphatase activity. Several cancer associated PTEN mutations do not affect PTEN catalytic activity. We propose to study the molecular basis of this phosphatase independent activity and the biological and molecular consequence of these cancer associated mutations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA082328-10
Application #
7561285
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
1999-08-01
Project End
2008-04-30
Budget Start
2008-03-24
Budget End
2008-04-30
Support Year
10
Fiscal Year
2007
Total Cost
$96,043
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Matsumoto, Akinobu; Pasut, Alessandra; Matsumoto, Masaki et al. (2017) mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 541:228-232
Noguera, Nélida Inés; Piredda, Maria Liliana; Taulli, Riccardo et al. (2016) PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity. Oncotarget 7:66386-66397
Tay, Yvonne; Pandolfi, Pier Paolo (2016) Posttranscriptional Regulation of PTEN by Competing Endogenous RNAs. Methods Mol Biol 1388:139-54
Lunardi, Andrea; Varmeh, Shohreh; Chen, Ming et al. (2015) Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer Discov 5:550-63
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Tay, Yvonne; Tan, Shen Mynn; Karreth, Florian A et al. (2014) Characterization of dual PTEN and p53-targeting microRNAs identifies microRNA-638/Dnm2 as a two-hit oncogenic locus. Cell Rep 8:714-22
Lunardi, Andrea; Webster, Kaitlyn A; Papa, Antonella et al. (2014) Role of aberrant PI3K pathway activation in gallbladder tumorigenesis. Oncotarget 5:894-900
Papa, Antonella; Wan, Lixin; Bonora, Massimo et al. (2014) Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 157:595-610
Tay, Yvonne; Rinn, John; Pandolfi, Pier Paolo (2014) The multilayered complexity of ceRNA crosstalk and competition. Nature 505:344-52

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