Physiological Functions of Pten in Mouse Tissues.

Abstract

ABSTRACT. PTEN is a tumor suppressor gene mutated in many human sporadic cancers and in hereditary cancer syndromes such as Cowden disease, Bannayan-Zonana syndrome and Lhermitte-Duclos disease. The major substrate of PTEN is PIP3, a second messenger molecule produced following PI3K activation induced by variety of stimuli. PIP3 activates the serine-threonine kinase PKB/Akt which is involved in anti-apoptosis, proliferation and oncogenesis. In mice, heterozygosity for a null mutation of Pten (Pten +/-mice) frequently leads to the development of a variety of cancers and autoimmune disease. Homozygosity for the null mutation (Pten -/-mice) results in early embryonic lethality, precluding the functional analysis of Pten in various organs. To investigate the physiological functions of Pten in viable mice, various tissue-specific Pten mutations have been generated using the Cre-loxP system. This review will summarize the phenotypes of conditional mutant mice lacking Pten function in specific tissues, and discuss how these phenotypes relate to the physiological roles of Pten in various organ systems.

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

“…18 As described earlier, expression of Egr1 in HT1080 human fibrosarcoma cells results in increased secretion of functional fibronectin 7,13 and activation of FAK. 45 Activated Akt is a major modulator of apoptosis at several levels (reviewed in Ruoslahti 18 and Kishimoto et al 47 ) (Figure 1). It phosphorylates and inactivates the proapoptotic factors BAD and Caspase 8.…”

Tumours and tremors: how PTEN regulation underlies both

“…Numerous conventional and conditional genetargeting murine models of pten deficiency have been generated to investigate the physiological functions of PTEN. Conventional gene-targeting of pten in all mouse tissues (pten À/À mice) results in developmental delay and lethality at embryonic days 6.5 -8.5 due to a failure in chorio-allantoic fusion (Kishimoto et al, 2003). However, pten þ /À mice eventually develop LOH of the remaining pten allele, leading to the appearance of tumours in the endometrium, liver, prostate, gastrointestinal tract, thyroid and thymus.…”

“…However, pten þ /À mice eventually develop LOH of the remaining pten allele, leading to the appearance of tumours in the endometrium, liver, prostate, gastrointestinal tract, thyroid and thymus. Interestingly, in addition to tumours, tissue-specific deletion of pten can result in hyperplasia, autoimmunity, glucose dysregulation or neurological deficits (Kishimoto et al, 2003).…”

“…Through its effects on PKB/Akt, PTEN can induce the activation of proapoptotic molecules such as Fas and bim, while promoting the inactivation of antiapoptotic molecules such as the bcl-2 family member Bad and the X-linked inhibitor of apoptosis (XIAP) that blocks caspase activation. As a result, pten þ /À mice are abnormally susceptible to Fas-mediated apoptosis, and ectopic expression of PTEN sensitises glioblastoma cells to irradiationand Fas-induced apoptosis characterised by increased caspase-3 activity (Kishimoto et al, 2003). PTEN also plays an important role in the induction of death in cells that lose contact with the extracellular matrix, a type of PCD called anoikis.…”

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

“…PI3K generates phosphatidylinositol (3,4,5)-triphosphate (PtdIns(3,4,5)P 3 ) from PtdIns(4,5)P 2 , and PtdIns (3,4,5) then transmits the signals through downstream effectors, including Akt, a serine/threonine kinase (Brazil et al, 2004). The physiological and pathological effects of PI3K/Akt signaling are counteracted by the tumor-suppressor PTEN, which dephosphorylates PtdIns(3,4,5)P 3 into PtdIns(4,5)P 2 (Kishimoto et al, 2003). PI3K/Akt signaling regulates self-renewal and differentiation capacity in the following stem cell systems.…”