Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 54

to the larger FKBP52 (26% identity) (Robson and James 2012 ). However, the
PPIase domain only shares 17 % identity with the FKBP52 PPIase region (Robson
and James 2012 ). The FKBPL TPR domain shares 33 % amino acid identity with
FKBP52 and has the ability to interact with Hsp90 stabilizing steroid hormone
receptor conformations as well as stabilizing newly synthesized p21 preventing its
degradation (Robson and James 2012 ; Jascur et al. 2005 ). There is conflicting data
on FKBPL and its role in conferring radiation resistance. Jascur et al. originally
showed that, in response to high-dose radiation, the FKBPL/Hsp90/p21 complex
stabilized p21 leading to G2 cell cycle arrest, which conferred a pro-survival ef-
fect. However, more recent data has demonstrated that there is a down-regulation
of p21 in response to radiation exposure and decreased p21 was involved in pro-
survival after radiation exposer (Chu et al. 2004 ; Robson et al. 1999 ; Robson et al.
2000 ). In addition to radiation resistance, FKBPL plays a significant role in tumor
progression (Robson et al. 1997 ; Robson et al. 1999 ; Robson et al. 2000 ; Jascur
et al. 2005 ). In tumor cells, FKBPL appears to participate in not only growth of the
tumor, but also in the sensitivity of the tumor to various chemotherapeutic agents
(Bublik et al. 2010 ). For example, high levels of GSTE-1 interact with the FKBPL/
Hsp90/p21 complex, which leads to p21 stabilization leading to resistance to the
chemotherapeutic agent Taxane (Bublik et al. 2010 ). Although the exact radio- and
chemo-protective role of FKBPL needs to be elucidated, the data clearly show that
FKBPL is an important factor in cell-cycle progression, cell survival, and tumor
progression.
Like other Hsp90-associated FKBP proteins, FKBPL also forms complexes
with various steroid hormone receptors (reviewed in Erlejman et al. 2014 ). FK-
BPL and Hsp90 appear to stabilize AR, ER, and GR/Hsp90 complexes (Sunnotel
et al. 2010 ; McKeen et al. 2008 ; McKeen et al. 2010 ). Similar to FKBP52, FKBPL
affects the AR-dependent expression of prostate-specific antigen (Sunnotel et al.
2010 ). Sunnotel et al. demonstrated that two populations of azoospermic males
had alterations in their FKBPL gene, which may alter FKBPL interaction with
AR and contribute to infertility in the two populations. FKBPL was also shown
to colocalize with the GR/Hsp90 complex (McKeen et al. 2008 ). Dexamethasone
treatment resulted in the colocalization of FKBPL and GR in the nucleus and the
up-regulation of GR-response genes in a prostate cancer cell line (McKeen et al.
2008 ). Translocation of the FKBPL/GR complex appears to be mediated by an
interaction with dynamitin motor proteins, similar to the mechanism described for
FKBP52 (McKeen et al. 2008 ).
FKBPL expression is regulated by estrogen and FKBPL functionally interacts
with the ER/Hsp90 complex (McKeen et al. 2010 ). In addition, FKBPL expres-
sion correlates with breast cancer tumor growth as FKBPL and ER expression
are inversely related; increased FKBPL levels lead to decreased ER expression
(McKeen et al. 2010 ; Abukhdeir et al. 2008 ). Overexpression of FKBPL is as-
sociated with increased survival of untreated breast cancer patients and sensi-
tizes cancer cells to the anti-proliferative effect of both tamoxifen and fulves-
trant, which promotes increased recurrence-free survival (McKeen et al. 2011 ;