Abstract
For proper development and tissue homeostasis, cell cycle progression is controlled by multilayered mechanisms. Recent studies using knock-out mice have shown that animals can develop relatively normally with deficiency for each of the G1/S-regulatory proteins, D-type and E-type cyclins, cyclin-dependent kinase 4 (Cdk4), and Cdk2. Although Cdk4-null mice show no embryonic lethality, they exhibit specific endocrine phenotypes, i.e. dwarfism, infertility, and diabetes. Here we have demonstrated that Cdk4 plays an essential non-redundant role in postnatal proliferation of the anterior pituitary. Pituitaries from wild-type and Cdk4-null embryos at embryonic day 17.5 are morphologically indistinguishable with similar numbers of cells expressing a proliferating marker, Ki67, and cells expressing a differentiation marker, growth hormone. In contrast, anterior pituitaries of Cdk4-null mice at postnatal 8 weeks are extremely hypoplastic with markedly decreased numbers of Ki67+ cells, suggesting impaired cell proliferation. Pituitary hyperplasia induced by transgenic expression of human growth hormone-releasing hormone (GHRH) is significantly diminished in the Cdk4+/- genetic background and completely abrogated in the Cdk4-/- background. Small interfering RNA (siRNA)-mediated knockdown of Cdk4 inhibits GHRH-induced proliferation of GH3 somato/lactotroph cells with restored expression of GHRH receptors. Cdk4 siRNA also inhibits estrogen-dependent cell proliferation in GH3 cells and closely related GH4 cells. In contrast, Cdk6 siRNA does not diminish proliferation of these cells. Furthermore, Cdk4 siRNA does not affect GHRH-induced proliferation of mouse embryonic fibroblasts or estrogen-dependent proliferation of mammary carcinoma MCF-7 cells. Taken together, Cdk4 is dispensable for prenatal development of the pituitary or proliferation of other non-endocrine tissues but indispensable specifically for postnatal proliferation of somato/lactotrophs.
Highlights
Proliferation-stimulatory and -inhibitory signals control the G1 phase of the cell cycle, which is critical for development and homeostasis of essentially all animal tissues [1]
Small numbers of growth hormone (GH)- and prolactin-immunoreactive cells are present in Cdk4Ϫ/Ϫ pituitaries, suggesting that cell fate determination to the somato/lactotroph lineages is still functional in the absence of cyclin-dependent kinase 4 (Cdk4)
At E17.5 the somatotroph population has yet to be fully expanded because the expression of the somatotroph-specific mitogen, growth hormone-releasing hormone (GHRH), is not increased until a later stage of development [17, 18]
Summary
Cyclin-dependent kinase; Rb, retinoblastoma gene product; MT, metallothionein; GH, growth hormone; GHRH, GH-releasing hormone; Ad GHRH-R, adenovirus encoding GHRH receptor; siRNA, small interfering ribonucleic acid; MEF, mouse embryonic fibroblast; BrdUrd, bromodeoxyuridine; TUNEL, terminal deoxynucleotidyltransferase-mediated nick-end labeling; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; E2, estrogen. We have reported that Cdk is required for hormonally regulated proliferation of somatotrophs and lactotrophs in postnatal pituitary glands, whereas Cdk is dispensable in embryonic development of the pituitary. Together with the requirement of Cdk for maintenance of postnatal pancreatic  cells [11, 12], the data suggest a unique nature of cell cycle control in particular endocrine tissues
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