Stefano Govoni, Italian pharmacologist, educator. Achievements include over 330 papers published in referred journals on topics including: dopaminergic transmission, neuropharmacology, neurobiology of aging and of Alzheimer's disease. Recipient Forein Correspondant, National Academy Pharmacy and Biochemistry Argentina, 2005. Member of Italian Society Pharmacology.
Several epidemiological studies show an inverse association between cancer and Alzheimer’s diseas... more Several epidemiological studies show an inverse association between cancer and Alzheimer’s disease (AD). It is debated whether this association is the consequence of biological mechanisms shared by both these conditions or may be related to the pharmacological treatments carried out on the patients. The latter hypothesis, however, is not sustained by the available evidence. Hence, the focus of this review is to analyze common biological mechanisms for both cancer and AD and to build up a biological theory useful to explain the inverse correlation between AD and cancer. The review proposes a hypothesis, according to which several molecular players, prominently PIN1 and p53, have been investigated and considered involved in complex molecular interactions putatively associated with the inverse correlation. On the other hand, p53 involvement in both diseases seems to be a consequence of the aberrant activation of other proteins. Instead, PIN1 may be identified as a novel key regulator at the crossroad between cancer and AD. PIN1 is a peptidyl-prolyl cis - trans isomerase that catalyzes the cis - trans isomerization, thus regulating the conformation of different protein substrates after phosphorylation and modulating protein function. In particular, trans -conformations of Amyloid Precursor Protein (APP) and tau are functional and “healthy”, while cis -conformations, triggered after phosphorylation, are pathogenic. As an example, PIN1 accelerates APP cis -to- trans isomerization thus favoring the non-amyloidogenic pathway, while, in the absence of PIN1, APP is processed through the amyloidogenic pathway, thus predisposing to neurodegeneration. Furthermore, a link between PIN1 and tau regulation has been found, since when PIN1 function is inhibited, tau is hyperphosphorylated. Data from brain specimens of subjects affected by mild cognitive impairment and AD have revealed a very low PIN1 expression. Moreover, polymorphisms in PIN1 promoter correlated with an increased PIN1 expression are associated with a delay of sporadic AD age of onset, while a polymorphism related to a reduced PIN1 expression is associated with a decreased risk of multiple cancers. In the case of dementias, in particular of Alzheimer’s disease, new biological markers and targets based on the discussed players can be developed based on a theoretical approach relying on different grounds compared to the past. An unbiased expansion of the rationale and of the targets may help to achieve in the field of neurodegenerative dementias similar advances to those attained in the case of cancer treatment.
<p>Dot blot analysis on protein extracts derived from controls (n = 9), EOSAD (n = 9) and A... more <p>Dot blot analysis on protein extracts derived from controls (n = 9), EOSAD (n = 9) and ADmut (n = 9) lymphocytes were performed using specific antibodies against oxidative stress markers: protein-bound HNE (<b>A</b>), 3NT (<b>B</b>) and PC (<b>C</b>). Tubulin expression was used to normalize the samples. * p<0,05 control vs ADmut.</p
Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic mark... more Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic marker and drug target in breast cancer (BC). High RACK1 expression is negatively associated with overall survival, as it seems to promote BC progression. In tumors, RACK1 expression is controlled by a complex balance between glucocorticoids and androgens. Given the fact that androgens and androgenic derivatives can inhibit BC cell proliferation and migration, the role of androgen signaling in regulating RACK1 transcription in mammary tumors is of pivotal interest. Here, we provide evidence that nandrolone (19-nortosterone) inhibits BC cell proliferation and migration by antagonizing the PI3K/Akt/NF-κB signaling pathway, which eventually results in RACK1 downregulation. We also show that nandrolone impairs the PI3K/Akt/NF-κB signaling pathway and decreases RACK1 expression via binding to the membrane-bound receptor, oxoeicosanoid receptor 1 (OXER1). High levels of OXER1 are observed in sever...
PurposeOxidative stress, inflammation, protein aggregation, are major features of Age‐related Mac... more PurposeOxidative stress, inflammation, protein aggregation, are major features of Age‐related Macular Degeneration (AMD). A primary system used by the RPE to neutralize oxidative stress and maintain cellular homeostasis is the transcription nuclear factor E2‐related factor 2 (Nrf2) pathway, whose impairment in AMD is documented. Many Nrf2 targets with a role in AMD are also regulated at post‐transcriptional level by the RNA‐binding protein HuR/ELAVL1. However, the role of HuR and post‐transcriptional control of gene expression in AMD is largely unexplored. We studied the pattern of HuR expression in vitro and in vivo contexts characterized by Nrf2 impairment, as well as in AMD human specimens.MethodsHuR protein pattern was evaluated by Western blot and immunostaining. Wild type (WT) and Nrf2‐deficient ARPE‐19 cells were used for in vitro study. Retinas from mice deficient in either Nrf‐2 (Nrf‐2 single knockout, sKO), or both Nrf‐2 and PGC‐1α (Nrf‐2/PGC‐1α double knockout, dKO) at on...
Several epidemiological studies show an inverse association between cancer and Alzheimer’s diseas... more Several epidemiological studies show an inverse association between cancer and Alzheimer’s disease (AD). It is debated whether this association is the consequence of biological mechanisms shared by both these conditions or may be related to the pharmacological treatments carried out on the patients. The latter hypothesis, however, is not sustained by the available evidence. Hence, the focus of this review is to analyze common biological mechanisms for both cancer and AD and to build up a biological theory useful to explain the inverse correlation between AD and cancer. The review proposes a hypothesis, according to which several molecular players, prominently PIN1 and p53, have been investigated and considered involved in complex molecular interactions putatively associated with the inverse correlation. On the other hand, p53 involvement in both diseases seems to be a consequence of the aberrant activation of other proteins. Instead, PIN1 may be identified as a novel key regulator at the crossroad between cancer and AD. PIN1 is a peptidyl-prolyl cis - trans isomerase that catalyzes the cis - trans isomerization, thus regulating the conformation of different protein substrates after phosphorylation and modulating protein function. In particular, trans -conformations of Amyloid Precursor Protein (APP) and tau are functional and “healthy”, while cis -conformations, triggered after phosphorylation, are pathogenic. As an example, PIN1 accelerates APP cis -to- trans isomerization thus favoring the non-amyloidogenic pathway, while, in the absence of PIN1, APP is processed through the amyloidogenic pathway, thus predisposing to neurodegeneration. Furthermore, a link between PIN1 and tau regulation has been found, since when PIN1 function is inhibited, tau is hyperphosphorylated. Data from brain specimens of subjects affected by mild cognitive impairment and AD have revealed a very low PIN1 expression. Moreover, polymorphisms in PIN1 promoter correlated with an increased PIN1 expression are associated with a delay of sporadic AD age of onset, while a polymorphism related to a reduced PIN1 expression is associated with a decreased risk of multiple cancers. In the case of dementias, in particular of Alzheimer’s disease, new biological markers and targets based on the discussed players can be developed based on a theoretical approach relying on different grounds compared to the past. An unbiased expansion of the rationale and of the targets may help to achieve in the field of neurodegenerative dementias similar advances to those attained in the case of cancer treatment.
<p>Dot blot analysis on protein extracts derived from controls (n = 9), EOSAD (n = 9) and A... more <p>Dot blot analysis on protein extracts derived from controls (n = 9), EOSAD (n = 9) and ADmut (n = 9) lymphocytes were performed using specific antibodies against oxidative stress markers: protein-bound HNE (<b>A</b>), 3NT (<b>B</b>) and PC (<b>C</b>). Tubulin expression was used to normalize the samples. * p<0,05 control vs ADmut.</p
Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic mark... more Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic marker and drug target in breast cancer (BC). High RACK1 expression is negatively associated with overall survival, as it seems to promote BC progression. In tumors, RACK1 expression is controlled by a complex balance between glucocorticoids and androgens. Given the fact that androgens and androgenic derivatives can inhibit BC cell proliferation and migration, the role of androgen signaling in regulating RACK1 transcription in mammary tumors is of pivotal interest. Here, we provide evidence that nandrolone (19-nortosterone) inhibits BC cell proliferation and migration by antagonizing the PI3K/Akt/NF-κB signaling pathway, which eventually results in RACK1 downregulation. We also show that nandrolone impairs the PI3K/Akt/NF-κB signaling pathway and decreases RACK1 expression via binding to the membrane-bound receptor, oxoeicosanoid receptor 1 (OXER1). High levels of OXER1 are observed in sever...
PurposeOxidative stress, inflammation, protein aggregation, are major features of Age‐related Mac... more PurposeOxidative stress, inflammation, protein aggregation, are major features of Age‐related Macular Degeneration (AMD). A primary system used by the RPE to neutralize oxidative stress and maintain cellular homeostasis is the transcription nuclear factor E2‐related factor 2 (Nrf2) pathway, whose impairment in AMD is documented. Many Nrf2 targets with a role in AMD are also regulated at post‐transcriptional level by the RNA‐binding protein HuR/ELAVL1. However, the role of HuR and post‐transcriptional control of gene expression in AMD is largely unexplored. We studied the pattern of HuR expression in vitro and in vivo contexts characterized by Nrf2 impairment, as well as in AMD human specimens.MethodsHuR protein pattern was evaluated by Western blot and immunostaining. Wild type (WT) and Nrf2‐deficient ARPE‐19 cells were used for in vitro study. Retinas from mice deficient in either Nrf‐2 (Nrf‐2 single knockout, sKO), or both Nrf‐2 and PGC‐1α (Nrf‐2/PGC‐1α double knockout, dKO) at on...
Uploads
Papers by Stefano Govoni