Cdk4 is indispensable for postnatal proliferation of the anterior pituitary

J Biol Chem. 2004 Dec 3;279(49):51100-6. doi: 10.1074/jbc.M409080200. Epub 2004 Sep 28.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis
  • Bromodeoxyuridine / pharmacology
  • CDC2-CDC28 Kinases / metabolism
  • Cell Cycle
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Coloring Agents / pharmacology
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / physiology*
  • Estrogens / metabolism
  • G1 Phase
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Ki-67 Antigen / biosynthesis
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Pituitary Gland / embryology*
  • Pituitary Gland / metabolism*
  • Proto-Oncogene Proteins / physiology*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Receptors, Neuropeptide / genetics
  • Receptors, Pituitary Hormone-Regulating Hormone / genetics
  • S Phase
  • Time Factors
  • Transgenes


  • Coloring Agents
  • Estrogens
  • Ki-67 Antigen
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone-Regulating Hormone
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • CDK4 protein, human
  • Cdk2 protein, mouse
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • somatotropin releasing hormone receptor
  • Bromodeoxyuridine