Post translational Modulations of PTEN and Their Implication in Cancer
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Post translational Modulations of PTEN and Their Implication in Cancer
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| Creator |
Ahmed, Syed Feroj
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| Subject |
Cell Biology & Physiology
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| Description |
PTEN since its identification has been in large associated with the control of human malignancies. The dominance of PTEN over the PI3K signaling cascade is mainly
responsible for rendering it the tumor suppressive role that results in the control of a wide array of physiological processes; growth, apoptosis, proliferation and migration. However, in recent years, PTEN has expanded its TENtacles in regulating processes like stem cell
population maintenance, genomic stability regulation and activation of ovarian follicle. Meanwhile, PTEN protein phosphatase activity has gained significant importance and is even capable of inhibiting cell migration irrespective of the Akt pathway. As a protein phosphatase, it targets among others SRC kinases, CREB in the nucleus thereby regulating migration of glioma cells. Crucial for PTEN to be able to render its functions properly is the
ability to translocate to different sub-cellular compartments of the cell and even out of it
through exosomes while retaining its phosphatase activity in the cells where it is internalized. Justifiably, PTEN has fast attained the stature of one of the prime regulators of the cell and therefore it needs to be subjected to intricate surveillance. Although, PTEN like other major players of the cell shows regulation at the transcriptional level as well as through epigenetic silencing, post-translational modifications of PTEN and
the associated localization based alterations in its activities have been the focal point of research on PTEN regulatory events. There have been reports that suggest for negligible PTEN expression although the transcript levels seemed to be good enough. Thus, this study aims to delineate the post-translational modulations of PTEN and their implication in cancer. The first two parts of the work provide insights into the post-translational
regulation of PTEN mainly by ubiquitination and ubiquitination-phosphorylation crosstalk. While in the third part, a strategy to stabilize PTEN has been established through an exosomes-mediated delivery of the intrinsic C-terminus domain of PTEN that causes tumor
inhibition. In the first part of the study, we show that CHIP, the chaperone-associated E3 ligase induces ubiquitination and proteasomal degradation of PTEN as well as regulates the turnover of the protein. It was apparent from our findings that PTEN transiently associates
with the molecular chaperones and thereby gets diverted to the degradation pathway through its interaction with CHIP. The TPR domain of CHIP and parts of the N-terminal
domain of PTEN are required for their interaction. Overexpression of CHIP leads to elevated ubiquitination and a shortened half-life of endogenous PTEN. On the other hand,
depletion of endogenous CHIP stabilizes PTEN. CHIP is also shown to regulate PTENdependent transcription presumably through its downregulation. PTEN shared an inverse
correlation with CHIP in human prostate cancer patient samples thereby triggering the prospects of a more complex mode of PTEN regulation in cancer.PTEN mutation is a frequent feature across a plethora of human cancers, the hot-spot being its C-terminus (CT) regulatory domain resulting in a much diminished level of protein expression. In the second part of the work, the presence of C-terminus mutations was confirmed through sequencing of different human tumor samples. CKII-mediated phosphorylation of PTEN at these sites makes it a loopy structure competing with the E3 ligases for binding to its lipid anchoring C2 domain. Accordingly, it was found that PTEN-CT
expressing stable cell lines could inhibit tumorigenesis in syngenic breast tumor mice models. The third part shows the strategy to design a novel exosome-mediated delivery of the
intrinsic PTEN domain, PTEN-CT into different cancer cells and observed reduced proliferation, migration and colony forming ability. The delivery of exosome containing
PTEN-CT to breast tumor mice model was found to result in significant regression in tumor size with the tumor sections showing increased apoptosis. Here, we also report for the first time an active PTEN when its C2 domain is bound by PTEN-CT, probably rendering its antitumorigenic
activities through the protein phosphatase activity. Therefore, therapeutic interventions that focuses on PTEN E3 ligase inhibition through exosome-mediated PTENCT
delivery can be a probable route in the treatment of cancers with low PTEN expression. Altogether, the findings emanating from this research work could be useful in designing therapeutic strategies against cancers showing low or negligible PTEN expression.
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| Date |
2015
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2335/1/Thesis_SF_Ahmed.pdf
Ahmed, Syed Feroj (2015) Post translational Modulations of PTEN and Their Implication in Cancer. PhD thesis, Calcutta Univesity. |
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| Relation |
http://www.eprints.iicb.res.in/2335/
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