Structured Reports for the Pathological Society Awards: Centenary
Fellowships, PhD Studentships & Small Grant Awards.
Reports from recipients of Centenary Fellowships, PhD studentships & Small Grants
should be set out using the following subheadings and should consist of:
Annual Reports: 1 A4 page of text
Final reports: 2 A4 pages of text
Title: The Role of TRAP1/Hsp75 chaperon protein in human cancer
Name & Address: Prof Kevin Gatter, NDCLS, John Radcliffe Hospital, Oxford,
OX3 9DU.
Background:
We made the novel observation that transcription and expression of Heat Shock
Protein (HSP) chaperones to tumour suppressor genes can be lost in cancer. This
could be a new oncogenic mechanism in which a tumour suppressor protein is
inactivated because of conformational changes in the absence of the appropriate
chaperone, rather than due to genetic or epigenetic insults. One of these HSPs is
TRAP1 (also known as Hsp75), chaperone to Retinoblastoma (Rb1).
Original Aims (copied from original application):
This project will investigate how the loss of TRAP1 expression affects cell growth “in
vitro” and how this relates to apoptosis, proliferation and hypoxia both “in vitro” and
“in vivo”.
1-To study the effects of TRAP1 on cell growth “in vitro” using the spheroid model.
2-To correlate TRAP1 expression with markers of proliferation, apoptosis and
hypoxia both “in vitro” and “in vivo” to understand better the conditions under which
TRAP1 may be oncogenic or anti-oncogenic.
3-To verify the hypothesis we raised that TRAP1 regulates the expression of JMY, a
putative regulator of cell motility and metastatic spread.
Results: The achievements to date are:
- A full characterization of the expression of hypoxia and angiogenesis related protein
on angiogenic and non angiogenic lung cancers has been concluded. Data show that
non-angiogenic tumours have a similar expression of HIF related proteins despite
their lack of angiogenesis but have a higher expression of p53. Sequencing data for
P53 shows that p53 is mostly germline in both tumour types suggesting that
differential expression of this protein is due to interactions with other proteins rather
than direct genetic damage (Manuscript in preparation)
-A Monoclonal Antibody against JMY (identified as possibly related to TRAP in earlier
studies) has been fully characterized. Its distribution on normal tissues and the main
types of human tumours has been investigated. Data from this first study suggests
that loss of nuclear JMY occurs during tumour progression as predicted by its
putative suppressive role as a p53 co factor. However higher cytoplasmic JMY has
been found in metastatic lesions suggesting another important role as a putative prometastatic gene (Manuscript in preparation)
- The relationship between JMY and TRAP1 has been clarified: Preliminary data
suggested an inverse relationship but actually our further studies show that there is a
direct correlation between TRAP1 and JMY and that the two proteins physically
interact.
- Spheroid growth experiments have been concluded and show that loss of TRAP1
reduces growth rate, Characterization of TRAP1 and JMY expression on the
spheroids is still in progress
Conclusions:
We have made substantial progress in understanding the role of TRAP1 and JMY
and their interactions in human tissues and tumours.
How Closely Have the Original Aims been Met:
Ms Adighibe has stuck closely to the three aims as outlined above and provided as
shown in the results a clear account of each of the three aims. She is now completing
her final experiments and actively writing her thesis for submission later this year.
We are very grasteful to the pathological society for its support of this work.
You may include up to 1 extra page for diagrams/images/tables and references.
Agreed by Research Subcommittee November 2009.