Stem Cell Factor/c-kit Up-regulates Cyclin D3 and Promotes Cell Cycle Progression via the Phosphoinositide 3-Kinase/p70 S6 Kinase Pathway in Spermatogonia

Li, Feng; Ravindranath, Neelakanta; Dym, Martin

doi:10.1074/jbc.m002218200

Cited by 225 publications

(185 citation statements)

References 27 publications

(27 reference statements)

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“…We also stimulated spermatogonia with 100 ng/ml of KL, a growth factor which stimulates proliferation and survival of spermatogonia. 21,31,32 Nuclear spreads were prepared from cells at the beginning and at the end of the culture time and probed with antibodies against the synaptonemal complex protein 3 (SCP3) to detect meiotic nuclei and to evaluate the degree of meiotic progression (Figs. 2 and 3B).…”

Section: Resultsmentioning

confidence: 99%

ATRA and KL promote differentiation toward the meiotic program of male germ cells.

Pellegrini¹,

Filipponi²,

Gori³

et al. 2008

Cell Cycle

107

144

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While it is known that Retinoic Acid (RA) induces meiosis in mouse female fetal gonads, the mechanisms which regulate this process during spermatogenesis are poorly understood. We show that the All trans RA derivative (ATRA) and Kit Ligand (KL) increase meiotic entry of postnatal mouse spermatogonia in vitro without synergism. Competence to enter meiosis is reached by spermatogonia only at the stage in which they undergo Kit-dependent divisions. Besides increasing Kit expression in spermatogonia, ATRA also upregulates KL expression in Sertoli cells. Both ATRA and KL increase the expression of Stimulated by Retinoic Acid Gene 8 and Dmc1, an early meiotic marker. A specific Kit tyrosine kinase inhibitor prevents the increase in the number of meiotic cells induced by both the two factors, suggesting that they converge on common Kit-dependent signalling pathways. Meiotic entry induced by ATRA and KL is independent from their ability to affect germ cell viability, and is mediated by the activation of PI3K and MAPK pathways through Kit autophosphorylation. ATRA-induced phosphorylation of the two downstream kinases is mediated by a non-genomic mechanism.These data suggest that RA may control the timing of meiosis by influencing both the somatic and the germ cell compartment of the postnatal testis through the activation of the KL/Kit system.

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Section: Resultsmentioning

confidence: 99%

ATRA and KL promote differentiation toward the meiotic program of male germ cells.

Pellegrini¹,

Filipponi²,

Gori³

et al. 2008

Cell Cycle

107

144

View full text Add to dashboard Cite

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“…Gamma-GT is connected with maturation and proliferation of Sertoli cells, CP-induced increases in its activity means damaged Sertoli cells and disturbed spermatogenesis. Sertoli cell secreted stem cell factors are important to regulate proliferation and differentiation of spermatogonial cells (23), however, CY blocks proliferation and differentiation of spermatogonial cells (24,25) through down-regulating the expression of stem cell factors in Sertoli cells. AKP and ACP are non-specifi c phosphatases released from injured degenerating cells and germ cells: increased activities of the two enzymes result in damage to seminiferous epithelium cells and original embryonic cells, a decrease in spermatogenetic time, and damage of reproductive function (26).…”

Section: Discussionmentioning

confidence: 99%

Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice

Le¹,

Luo²,

Gu³

et al. 2015

BLL

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Cyclophosphamide (CP) is a commonly used antitumour and immunosuppressive drug, but it is inevitable that the chemotherapeutic agent may cause long-term or permanent reproductive damage on young male patients through inducing oxidative stress in the testes. Squid ink polysaccharides (SIP), a newly found marine glycosaminoglycon have been proved to have antioxidant capabilities and chemotherapy-protective activities on model animals in our recent investigations. This study was conducted to assess whether or not SIP could protect male mice against gonadotoxicity during CP exposure. Sexually mature male Kunming mice were allocated to one of four groups. CP was abdominally administered at dose of 15 mg/kg body weight to two groups of mice for ten weeks, once a week, one group of mice received SIP at dose of 80 mg/kg body weight by gavage for ten weeks, once a day. The other two groups comprised a vehicle treated group and an SIP treated group. Toxicity of CP and protective activity of SIP on the testes were assessed by: sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sex hormone content, and histopathological features. Data showed CP-induced, serious negative changes on murine sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sexual hormone contents, and histopathological features which were all signifi cantly impaired by SIP. This study found that SIP were demonstrated to offer protective effects against CP-induced toxicity on testes in mice (Tab. 2, Fig. 3, Ref. 29). Text in PDF www.elis.sk.

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“…However, in systems in which cyclin D3 promotes cell cycle progression, its expression is highly dependent on mitogenic stimuli, particularly activation of the PI3K pathway. [50][51][52][53] Thus, cells which use cyclin D3 to regulate passage through the G1 restriction point appear to have evolved mechanisms to markedly induce this protein in response to PI3K signaling. In hepatocytes, cyclin D3 was expressed in quiescent cells and was only modestly responsive to EGF, insulin, or PI3K signaling, suggesting that it does not play a critical role in regulating progression through G1 phase in response to these signals.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of cyclins D1 and D3 in hepatocyte proliferation

et al. 2002

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Substantial evidence suggests that cyclin D1 plays a pivotal role in the control of the hepatocyte cell cycle in response to mitogenic stimuli, whereas the closely related protein cyclin D3 has not been extensively evaluated. In the current study, we examined the regulation of cyclins D1 and D3 during hepatocyte proliferation in vivo after 70% partial hepatectomy (PH) and in culture. In contrast to cyclin D1, which was nearly undetectable in quiescent liver and substantially up-regulated after PH, cyclin D3 was constitutively expressed and induced only modestly. In the regenerating liver, the concentration of cyclin D3 was only about 10% of that of cyclin D1. Cyclin D1 formed complexes primarily with cyclin-dependent kinase 4 (cdk4), which were markedly activated in the regenerating liver and readily sequestered the cell cycle inhibitory proteins, p21 and p27. Cyclin D3 bound to both cdk4 and cdk6. Cyclin D3/cdk6 activity was readily detectable in quiescent liver and changed little after PH, and this complex appeared to play a minor role in sequestering p21 and p27. In cultured hepatocytes, epidermal growth factor or insulin had little effect, but the combination of these agents substantially induced cyclin D1 and cell cycle progression. Inhibition of Mek1 or phosphoinositide 3-kinase markedly inhibited cyclin D1 expression and replication. In contrast, cyclin D3 was expressed in the absence of mitogens and was only modestly affected by these manipulations. In addition, growth-inhibitory extracellular matrix conditions inhibited cyclin D1 but not cyclin D3 expression. In conclusion, these results support the concept that cyclin D1 is critically regulated by extracellular stimuli that control proliferation, whereas cyclin D3 is regulated through different pathways and plays a distinct role in the liver. (HEPATOLOGY 2002;36:30-38.) P rogression through the cell cycle is regulated by the activity of protein kinase complexes consisting of cyclins and cyclin-dependent kinases (cdk), which are activated at distinct stages of proliferation. 1-3 During G1 phase, mitogens up-regulate the D-type cyclins, which form complexes with cdk4 and cdk6 that phosphorylate the retinoblastoma protein (Rb) and the related p107 and p130 proteins. The three D-type cyclins (D1, D2, and D3) display significant homology, suggesting that they may perform overlapping functions. 4,5 This concept is supported by studies showing that cyclin D1 or D2 knockout mice are viable and show relatively limited phenotypic effects. 6-8 On the other hand, the expression patterns of the D-type cyclins vary widely in different cell types, suggesting that they have distinct functions in specific tissues. Although cyclins D1 and D2 clearly regulate cell proliferation, the role of cyclin D3 has not been well characterized. Cyclin D3 is implicated in cell cycle control in some types of cells, but it is also widely expressed in nonreplicating mammalian tissues, indicating that it plays a role in quiescent cells. 9,10 Indeed, cyclin D3 is up-regulated during te...

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Stem Cell Factor/c-kit Up-regulates Cyclin D3 and Promotes Cell Cycle Progression via the Phosphoinositide 3-Kinase/p70 S6 Kinase Pathway in Spermatogonia

Cited by 225 publications

References 27 publications

ATRA and KL promote differentiation toward the meiotic program of male germ cells.

ATRA and KL promote differentiation toward the meiotic program of male germ cells.

Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice

Differential regulation of cyclins D1 and D3 in hepatocyte proliferation

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