Dynamin II is required for 17β-estradiol signaling and autophagy-based ERα degradation

Abstract

17β-estradiol (E2) regulates diverse physiological effects, including cell proliferation, by binding to estrogen receptor α (ERα). ERα is both a transcription factor that drives E2-sensitive gene expression and an extra-nuclear localized receptor that triggers the activation of diverse kinase cascades. While E2 triggers cell proliferation, it also induces ERα degradation in a typical hormone-dependent feedback loop. Although ERα breakdown proceeds through the 26S proteasome, a role for lysosomes and for some endocytic proteins in controlling ERα degradation has been reported. Here, we studied the role of the endocytic protein dynamin II in E2-dependent ERα signaling and degradation. The results indicate that dynamin II siRNA-mediated knock-down partially prevents E2-induced ERα degradation through the inhibition of an autophagy-based pathway and impairs E2-induced cell proliferation signaling. Altogether, these data demonstrate that dynamin II is required for the E2:ERα signaling of physiological functions and uncovers a role for autophagy in the control of ERα turnover.

A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells

“…The apparent paradox that 26S proteasome inhibitors reduce the levels of ERα, which turnover is, at least in part, controlled by the 26S proteasome itself can be reconciled by considering that the irreversible inhibition of 26S proteasome leads to a high accumulation of ubiquitinated species, which cells remove by activating autophagy [40,41]. In this respect, ERα basal turnover is under the control of the autophagic flux [11] and both carfilzomib and bortezomib can activate autophagy [42,43].…”

“…Some ERα ligands (e.g., 4OH-tamoxifen and faslodex) change ERα levels and block E2induced cell proliferation. Recently, we and others have also shown that the interference with pathways not related to ERα obtained by specific molecules (e.g., chloroquine) or by selective gene knock-down (e.g., siRNA against clathrin, caveolins, and dynamin II) modifies ERα intracellular content and prevents E2 proliferative effects [1,4,[11][12][13][14][15][16][17][18]. On this basis, we have proposed [1,11,25] that the modulation of ERα intracellular concentration in BC cells could be used as a pharmacological target to identify anti-tumor drugs.…”

The anti-viral dynamin family member MxB participates in mitochondrial integrity

“…Central to these alterations in mitochondrial form are the dynamin family of large GTPases, which are known to bind and remodel membranes 4,5 . Distinct from the conventional dynamins (Dyn1, 2, 3) that are known to support membrane scission at distinct cellular sites such as the plasma membrane 6 , the Golgi apparatus 7 , as well as endosomes 8 and autolysosomes [9][10][11] , the dynamin-related proteins have been implicated in the dynamics of both mitochondria 12 and peroxisomes 13 . Although highly conserved within the N-terminal GTPase domains, these dynamin-related proteins are only modestly conserved in the middle domain and generally lack pleckstrin binding and proline-rich domains found in the conventional family members.…”

Longitudinal whole-exome sequencing of cell-free DNA unravels the metastatic evolutionary dynamics of BRCA2-mutated breast cancer

“…Putative pathogenic mutations were detected in DNM2 (p.G146D), DCC (p.E495K) and ATP1A1 (p.W105X) in the LR and B3 and B8 plasma samples but were not present in the PT, which suggests evidence of tumor evolution and an implication with cancer relapse after many years dormant. The DNM2 gene has been linked with cell migration and metastasis, receptor endocytosis and with resistance to endocrine therapy receptor endocytosis 24,25 . The DCC gene is frequently deleted or its expression reduced in breast cancer 26 .…”