Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

Kapitansky, Oxana; Sragovich, Shlomo; Jaljuli, Iman; Hadar, Adva; Giladi, Eliezer; Gozes, Illana

doi:10.3390/ijms21186715

Cited by 18 publications

(15 citation statements)

References 72 publications

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“…A recent study showed that the expression of ADNP enhanced the adaptive ability of malignant peripheral nerve sheath tumors to survive in a malignant environment [16, 35] [16]. The expression of ADNP in bladder was related to age and sex, and is higher in young men [36]. Here we found that the high expression of ADNP leaded to unfavorable prognosis in patients treated with chemotherapy.…”

Section: Discussionsupporting

confidence: 57%

ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway

Xie¹,

Zhu²,

Zang³

et al. 2021

J. Cancer

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Activity-dependent neuroprotective protein (ADNP) is vital for embryonic development and brain formation. Besides, the upregulated expression of ADNP enhances tumorigenesis in some human tumors like bladder cancer (BC). However, the potential roles of ADNP in drug resistance and the related mechanisms in BC is unknown. We performed this study to elucidate the influence of ADNP in the chemoresistance of BC and tried to explore the underlying molecular mechanism. The expressions of ADNP in BC from progression and non-progression patient specimens were measured by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). In vitro experiments including colony formation, cell counting kit-8 (CCK-8), wound healing, and in vivo tumorigenesis assay were performed to explore the effects of ADNP on chemoresistance of BC. The impacts of ADNP on TGF-β/Smad signaling pathways were explored by western blot. Our results showed that the expression of ADNP mRNA and protein were significantly upregulated in BC tissues of the patients who suffered tumor-progression via RT-PCR and western blot. Cox regression survival analysis revealed that patients with high ADNP expression closely linked to shorter tumor-free survival. ADNP downregulation in BC showed more sensitive to cisplatin in vivo, while ADNP overexpression showed the opposite results. Additionally, we confirmed that ADNP promoted cell migration and EMT, thereby inducing cisplatin resistance, which may be related to TGF-β / Smad signaling pathway.

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Section: Discussionsupporting

confidence: 57%

ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway

Xie¹,

Zhu²,

Zang³

et al. 2021

J. Cancer

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“…These are coupled to NAP enhancement of ADNP interaction with microtubule‐associated protein 1 light chain 3 (LC3) (Merenlender‐Wagner et al, 2015) constituting the autophagosome membrane, indicative of control of fundamental cellular processes. These interactions are further associated with ADNP/NAP control of gene expression central to brain/body functions (Amram et al, 2016; Hacohen‐Kleiman et al, 2018, 2019; Kapitansky, Karmon et al, 2020; Kapitansky, Sragovich et al, 2020; Karmon et al, 2022; Sragovich et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity‐dependent neuroprotective protein (ADNP) causes a mild developmental syndrome

Gozes

Shazman

2023

Eur J of Neuroscience

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NAP (NAPVSIPQ, drug candidate name, davunetide) is the neuroprotective fragment of activity-dependent neuroprotective protein (ADNP). Recent studies identified NAPVSIP as a Src homology 3 (SH3) domain-ligand association site, responsible for controlling signalling pathways regulating the cytoskeleton. Furthermore, the SIP motif in NAP/ADNP was identified as crucial for direct microtubule end-binding protein interaction facilitating microtubule dynamics and Tau microtubule interaction, at the microtubule end-binding protein site EB1 and EB3. Most de novo ADNP mutations reveal heterozygous STOP or frameshift STOP aberrations, driving the autistic/intellectual disability-related ADNP syndrome. Here, we report for the first time on a de novo missense mutation, resulting in ADNP containing NAPVISPQE instead of NAPVSIPQQ, in a child presenting developmental hypotonia, possibly associated with inflammation affecting food intake in early life coupled with fear of peer interactions and suggestive of a novel case of the ADNP syndrome. In silico modelling showed that the mutation Q (polar side chain) to E (negative side chain) affected the electrostatic characteristics of ADNP (reducing, while scattering the electrostatic positive patch). Comparison with the most prevalent pathogenic ADNP mutation, p.Tyr719*, indicated a further reduction in the electrostatic patch. Previously, exogenous NAP partially ameliorated deficits associated with ADNP p.Tyr719* mutations in transfected cells and in CRISPR/Cas9 genome edited cell and mouse models. These findings stress the importance of the NAP sequence in ADNP and as a future putative therapy for the ADNP syndrome.

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“…More than 400 genes are regulated by ADNP, which are critical for brain formation, organ development, cognition, and motor function (6,(13)(14)(15)(16). In the nucleus, ADNP is a member of a chromatin remodeling complex that is responsible for RNA transcription and splicing (13,(17)(18)(19).…”

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confidence: 99%

The ADNP Syndrome and CP201 (NAP) Potential and Hope

Gozes

2020

Front. Neurol.

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Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Original data showed that Adnp+/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome.

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Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

Cited by 18 publications

References 72 publications

ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway

ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway

A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity‐dependent neuroprotective protein (ADNP) causes a mild developmental syndrome

The ADNP Syndrome and CP201 (NAP) Potential and Hope

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