Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27 KIP1

FSH, acting through multiple signaling pathways, regulates the proliferation and growth of granulosa cells, which are critical for ovulation. The present study investigated whether AMP-activated protein kinase (AMPK), which controls the energy balance of the cell, plays a role in FSH-mediated increase in granulosa cell proliferation. Cells isolated from immature rat ovaries were grown in serum-free, phenol red free DMEM-F12 and were treated with FSH (50 ng/ml) for 0, 5, and 15 min. Western blot analysis showed a significant reduction in AMPK activation as observed by a reduction of phosphorylation at thr 172 in response to FSH treatment at all time points tested. FSH also reduced AMPK phosphorylation in a dose-dependent manner with maximum inhibition at 100 ng/ml. The chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, 0.5 mm) increased the cell cycle inhibitor p27 kip expression significantly, whereas the AMPK inhibitor (compound C, 20 μm) and FSH reduced p27kip expression significantly compared with control. FSH treatment resulted in an increase in the phosphorylation of AMPK at ser 485/491 and a reduction in thr 172 phosphorylation. Inhibition of Akt phosphorylation using Akt inhibitor VIII reversed the inhibitory effect of FSH on thr 172 phosphorylation of AMPK, whereas ERK inhibitor U0126 had no effect. These results show that FSH, through an Akt-dependent pathway, phosphorylates AMPK at ser 481/495 and inhibits its activation by reducing thr 172 phosphorylation. AMPK activation by 5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside treatment resulted in a reduction of cell cycle regulatory protein cyclin D2 mRNA expression, whereas FSH increased the expression by 2-fold. These results suggest that FSH promotes granulosa cell proliferation by increasing cyclin D2 mRNA expression and by reducing p27 kip expression by inhibiting AMPK activation through an Akt-dependent pathway. FSH stimulates granulosa cell proliferation by reducing cell cycle inhibitor p27 kip through AMP kinase inhibition.

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Concise synthesis of the cell cycle inhibitor demethoxyfumitremorgin C

Tetrahedron Letters ◽

10.1016/s0040-4039(97)00892-7 ◽

1997 ◽

Vol 38 (24) ◽

pp. 4327-4328 ◽

Cited By ~ 26

Author(s):

Haishan Wang ◽

Arasu Ganesan

Keyword(s):

Cell Cycle ◽

Cell Cycle Inhibitor

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Cell cycle inhibitor p21/ WAF1/ CIP1 as a cofactor of MITF expression in melanoma cells

Pigment Cell & Melanoma Research ◽

10.1111/j.1755-148x.2010.00670.x ◽

2010 ◽

Vol 23 (2) ◽

pp. 238-251 ◽

Cited By ~ 12

Author(s):

Blanka Šestáková ◽

Lubica Ondrušová ◽

Jiri Vachtenheim

Keyword(s):

Cell Cycle ◽

Melanoma Cells ◽

Cell Cycle Inhibitor ◽

P21 Waf1 ◽

Mitf Expression

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Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus

European Journal of Cancer ◽

10.1016/j.ejca.2006.03.015 ◽

2006 ◽

Vol 42 (12) ◽

pp. 1875-1880 ◽

Cited By ~ 121

Author(s):

I. Duran ◽

L.L. Siu ◽

A.M. Oza ◽

T.-B. Chung ◽

J. Sturgeon ◽

...

Keyword(s):

Cell Cycle ◽

Lung Toxicity ◽

Cell Cycle Inhibitor

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Regulation of the cell cycle inhibitor p27 and its ubiquitin ligase Skp2 in differentiation of human embryonic stem cells

The FASEB Journal ◽

10.1096/fj.06-7758com ◽

2007 ◽

Vol 21 (11) ◽

pp. 2807-2817 ◽

Cited By ~ 40

Author(s):

Dana Egozi ◽

Maanit Shapira ◽

Galit Paor ◽

Ofer Ben‐Izhak ◽

Karl Skorecki ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Ubiquitin Ligase ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Cell Cycle Inhibitor

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THE CELL CYCLE INHIBITOR P27KIP1 MODULATES THE CONTRIBUTION OF BONE MARROW DERIVED CELLS TO THE NEOINTIMA DURING ARTERIAL WOUND REPAIR

Cardiovascular Pathology ◽

10.1016/j.carpath.2004.03.351 ◽

2004 ◽

Vol 13 (3) ◽

pp. 116

Author(s):

Manfred Boehm ◽

Andrea C True ◽

Michelle Olive ◽

Martin F Crook ◽

Hong San ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Wound Repair ◽

Cell Cycle Inhibitor ◽

Bone Marrow Derived Cells

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Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

10.1101/470013 ◽

2018 ◽

Cited By ~ 5

Author(s):

Evgeny Zatulovskiy ◽

Daniel F. Berenson ◽

Benjamin R. Topacio ◽

Jan M. Skotheim

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Cell Growth ◽

Cell Size ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Inverse Correlation ◽

Cell Types ◽

Similar Amount ◽

Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

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