Inhibition of neuronal phenotype by PTEN in PC12 cells

Musatov, Sergei; Roberts, James W.; Brooks, Andrew I.; Pena, John; Betchen, Simone; Pfaff, Donald W.; Kaplitt, Michael G.

doi:10.1073/pnas.0308289101

Cited by 66 publications

(48 citation statements)

References 33 publications

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“…3 days), although S100B significantly increased Akt phosphorylation in both the absence and presence of NGF, NGF did not cause Akt inactivation (Fig. 5A), in agreement with the known ability of NGF to determine early and transient PC12 cell proliferation and confer resistance against apoptotic stimuli on PC12 cells via PI3-K/Akt activation (35)(36)(37)(38). However, NGF up-regulated p21 WAF1 expression (Fig.…”

Section: Fig 7 S100b Does Not Affect P53supporting

confidence: 83%

S100B Increases Proliferation in PC12 Neuronal Cells and Reduces Their Responsiveness to Nerve Growth Factor via Akt Activation

Arcuri

Bianchi

Brozzi

et al. 2005

Journal of Biological Chemistry

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S100B is a Ca 2؉ -modulated protein of the EF-hand type expressed in high abundance in a restricted set of cell types including certain neuronal populations. S100B has been suggested to participate in cell cycle progression, and S100B levels are high in tumor cells, compared with normal parental cells. We expressed S100B in the neuronal cell line PC12, which normally does not express the protein, by the Tet-Off technique, and found the following: (i) proliferation was higher in S100B ؉ PC12 cells than in S100B ؊ PC12 cells; (ii) nerve growth factor (NGF), which decreased the proliferation of S100B ؊ PC12 cells, was less effective in the case of S100B ؉ PC12 cells; (iii) expression of S100B made PC12 cells resistant to the differentiating effect of NGF; and (iv) interruption of S100B expression did not result in an immediate restoration of PC12 cell sensitivity to the differentiating effect of NGF. Expression of S100B in PC12 cells resulted in activation of Akt; increased levels of p21 WAF1 , an inhibitor of cyclin-dependent kinase (cdk) 2 and a positive regulator of cdk4; increased p21 WAF1 -cyclin D1 complex formation; and increased phosphorylation of the retinoblastoma suppressor protein, Rb. These S100B-induced effects, as well as the reduced ability of S100B ؉ PC12 cells to respond to NGF, were dependent on Akt activation because they were remarkably reduced or abrogated in the presence of LY294002, an inhibitor of the Akt upstream kinase phosphatidylinositol 3-kinase. Thus, S100B might promote cell proliferation and interfere with NGF-induced PC12 cell differentiation by stimulating a p21 WAF1 /cyclin D1/ cdk4/Rb/E2F pathway in an Akt-mediated manner. S100B, a member of a multigenic family of Ca 2ϩ -modulated proteins of the EF-hand type with both intracellular and extracellular regulatory activities, is expressed in varying abundance in astrocytes, Schwann cells, adipocytes, melanocytes, chondrocytes, skin Langerhans cells, lymphocyte subpopulations, skeletal muscle cells, and many neuronal populations (1, 2). Several intracellular target proteins have been identified for S100B (1, 2), many of which share a consensus sequence (3), and S100B has been shown to regulate protein phosphorylation, the dynamics of cytoskeleton components, Ca 2ϩ homeostasis, some enzyme activities, and transcription factors (1, 2). Moreover, S100B has been shown to be secreted by astrocytes, thereby affecting neuronal, astrocyte, and microglia functions within the brain (1, 2). S100B likely can be released by S100B-expressing cells outside the nervous system because it is found in normal serum (1), thereby affecting functions of non-nervous cells (4).Among the intracellular regulatory roles attributed to S100B is its participation in cell cycle progression. It has long been known that S100B levels are high in tumor cells, compared with normal parental cells (1, 2), and inhibition of S100B synthesis in an astrocyte cell line results in a decreased proliferation (5). However, the molecular mechanism underlying the potential role of ...

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Section: Fig 7 S100b Does Not Affect P53supporting

confidence: 83%

S100B Increases Proliferation in PC12 Neuronal Cells and Reduces Their Responsiveness to Nerve Growth Factor via Akt Activation

Arcuri

Bianchi

Brozzi

et al. 2005

Journal of Biological Chemistry

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“…In contrast to synaptojanin 1, rSac3 colocalizes with markers specific for organelles including ER, Golgi complex and recycling endosomes (Figure 3 trafficking. Previous work has also indicated that other PIPPases, such as inositol polyphosphate 5-phosphatase and PTEN, function as PI(3)K pathway inhibitors and inhibit neurite outgrowth in PC12 cells [55,56]. Considering that both of these two PIPPases are not Sac domain proteins and hydrolyze PI(3,4,5)P 3 , our work reveals that rSac3 is a 3-Pi and 4-Pi PIPPase, and may promote neurite outgrowth through a different pathway.…”

Section: Possible Function Of Rsac3mentioning

confidence: 53%

rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells

et al. 2007

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Sac domain-containing proteins belong to a newly identified family of phosphoinositide phosphatases (the PIPPase family). Despite well-characterized enzymatic activity, the biological functions of this mammalian Sac domain PIPPase family remain largely unknown. We identified a novel Sac domain-containing protein, rat Sac3 (rSac3), which is widely expressed in various tissues and localized to the endoplasmic reticulum, Golgi complex and recycling endosomes. rSac3 displays PIPPase activity with PI(3)P, PI(4)P and PI(3,5)P 2 as substrates in vitro, and a mutation in the catalytic core of the Sac domain abolishes its enzymatic activity. The expression of rSac3 is upregulated during nerve growth factor (NGF)-stimulated PC12 cell neuronal differentiation, and overexpression of this protein promotes neurite outgrowth in PC12 cells. Conversely, inhibition of rSac3 expression by antisense oligonucleotides reduces neurite outgrowth of NGFstimulated PC12 cells, and the active site mutation of rSac3 eliminates its neurite-outgrowth-promoting activity. These results indicate that rSac3 promotes neurite outgrowth in differentiating neurons through its PIPPase activity, suggesting that Sac domain PIPPase proteins may participate in forward membrane trafficking from the endoplasmic reticulum and Golgi complex to the plasma membrane, and may function as regulators of this crucial process of neuronal cell growth and differentiation.

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“…Many reports have suggested that PTEN plays a critical role in brain development and cell phenotype changes [7,14,15]. In order to further investigate the role of PTEN in cAMP-regulated cell growth, we performed western blotting analyses using the phospho-specific antibodies, phospho-PTEN (Ser380) antibody and phospho-Akt (Ser473) antibody.…”

Section: Camp-stimulating Agents Promote Morphological Changesmentioning

confidence: 99%

Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells

Sugimoto¹,

Miwa²,

Ohno‐Shosaku³

et al. 2011

Neuroscience Letters

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Inhibition of neuronal phenotype by PTEN in PC12 cells

Cited by 66 publications

References 33 publications

S100B Increases Proliferation in PC12 Neuronal Cells and Reduces Their Responsiveness to Nerve Growth Factor via Akt Activation

S100B Increases Proliferation in PC12 Neuronal Cells and Reduces Their Responsiveness to Nerve Growth Factor via Akt Activation

rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells

Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells

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