Cell Cycle, Cancer and Aging

CellCycle280-220Cell division requires faithful duplication of the genome as chromatin, and subsequent partitioning of chromosomes into progeny cells at mitosis. Cell cycle progression is stringently regulated and mechanisms that ensure the fidelity of this process are often deregulated in cancer. Normal cells are growth factor dependent and commit to initiate DNA replication at the G1/S phase transition. This growth-factor dependent control of the cell cycle is abrogated in cancer cells. Our recent studies have established that pluripotent stem cells have an abbreviated cell cycle due to a reduced G1 phase.

All dividing cells must package newly replicated DNA into chromatin during S phase, which necessitates the expression of multiple histone genes that encode the core nucleosomal proteins. Because transcription of histone genes is tightly coupled with the onset of DNA replication at the G1/S phase transition, we have pioneered the use of histone H4 genes as a paradigm for cell cycle control of transcription. These studies have resulted in the definition of a new cell cycle regulatory signaling pathway (Cyclin E-CDK2-NPAT-HiNFP axis). This pathway converges on subnuclear structures referred to as Histone Locus Bodies that contain histone gene clusters and the regulatory machinery for transcribing and processing of histone mRNAs (see Nuclear Structure and Function). Currently, we are examining cell cycle control in vivo during the earliest stages of embryonic development from the zygote to the blastocyst using conditional null mouse models lacking critical gene regulators.

Beyond defining basic mechanisms of cell cycle control in cancer cells and pluripotent embryonic stem cells, we are also addressing broader physiological processes linked to cancer and regenerative medicine. For example, tumor progression and cancer metastasis are examined in immune-deficient mouse models (see Musculoskeletal Biology and Pathology). Moreover, we are examining mechanisms of stem cell self-renewal and expansion of lineage-committed cells as it relates to regenerative medicine and aging (see Stem Cells and Regenerative Medicine).

Landmark Papers

  • Qiao M, Wang Y, Xu X, Lu J, Dong Y, Tao W, Stein J, Stein GS, Iglehart JD, Shi Q, Pardee AB. Mst1 is an interacting protein that mediates PHLPPs’ induced apoptosis. Mol Cell. 2010 May 28;38(4):512-23.

  • Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, Pratap J, Keller E, Stein GS, Lian JB. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 2010 Feb 11;29(6):811-21.

  • Zaidi SK, Dowdy CR, van Wijnen AJ, Lian JB, Raza A, Stein JL, Croce CM, Stein GS. Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network. Cancer Res. 2009 Nov 1;69(21):8249-55.

  • Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, Hussain S, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 2008 Oct 1;68(19):7795-802.

  • Medina R, van der Deen M, Miele-Chamberland A, Xie RL, van Wijnen AJ, Stein JL, Stein GS. The HiNF-P/p220NPAT cell cycle signaling pathway controls nonhistone target genes. Cancer Res. 2007 Nov 1;67(21):10334-42.

  • Becker KA, Stein JL, Lian JB, van Wijnen AJ, Stein GS. Establishment of histone gene regulation and cell cycle checkpoint control in human embryonic stem cells. J Cell Physiol. 2007 Feb;210(2):517-26.

  • Miele A, Braastad CD, Holmes WF, Mitra P, Medina R, Xie R, Zaidi SK, Ye X, Wei Y, Harper JW, van Wijnen AJ, Stein JL, Stein GS. HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition. Mol Cell Biol. 2005 Jul;25(14):6140-53.

  • Mitra P, Xie RL, Medina R, Hovhannisyan H, Zaidi SK, Wei Y, Harper JW, Stein JL, van Wijnen AJ, Stein GS. Identification of HiNF-P, a key activator of cell cycle-controlled histone H4 genes at the onset of S phase. Mol Cell Biol. 2003 Nov;23(22):8110-23.

  • Hovhannisyan H, Cho B, Mitra P, Montecino M, Stein GS, Van Wijnen AJ, Stein JL. Maintenance of open chromatin and selective genomic occupancy at the cell cycle-regulated histone H4 promoter during differentiation of HL-60 promyelocytic leukemia cells. Mol Cell Biol. 2003 Feb;23(4):1460-9.

  • Shopland LS, Byron M, Stein JL, Lian JB, Stein GS, Lawrence JB. Replication-dependent histone gene expression is related to Cajal body (CB) association but does not require sustained CB contact. Mol Biol Cell. 2001 Mar;12(3):565-76.

  • Vaughan PS, Aziz F, van Wijnen AJ, Wu S, Harada H, Taniguchi T, Soprano KJ, Stein JL, Stein GS. Activation of a cell-cycle-regulated histone gene by the oncogenic transcription factor IRF-2. Nature. 1995 Sep 28;377(6547):362-5.

  • Ramsey-Ewing A, Van Wijnen AJ, Stein GS, Stein JL. Delineation of a human histone H4 cell cycle element in vivo: the master switch for H4 gene transcription. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4475-9.

  • van Wijnen AJ, Choi TK, Owen TA, Wright KL, Lian JB, Jaenisch R, Stein JL, Stein GS. Involvement of the cell cycle-regulated nuclear factor HiNF-D in cell growth control of a human H4 histone gene during hepatic development in transgenic mice. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2573-7.

  • van Wijnen AJ, Massung RF, Stein JL, Stein GS. Human H1 histone gene promoter CCAAT box binding protein HiNF-B is a mosaic factor. Biochemistry. 1988 Aug 23;27(17):6534-41.

  • Lawrence JB, Singer RH, Villnave CA, Stein JL, Stein GS. Intracellular distribution of histone mRNAs in human fibroblasts studied by in situ hybridization. Proc Natl Acad Sci U S A. 1988 Jan;85(2):463-7.

  • Lichtler AC, Sierra F, Clark S, Wells JR, Stein JL, Stein GS. Multiple H4 histone mRNAs of HeLa cells are encoded in different genes. Nature. 1982 Jul 8;298(5870):195-8.

  • Marashi F, Baumbach L, Rickles R, Sierra F, Stein JL, Stein GS. Histone proteins in HeLa S3 cells are synthesized in a cell cycle stage specific manner. Science. 1982 Feb 5;215(4533):683-5.

  • Thompson JA, Stein JL, Kleinsmith LJ, Stein GS. Activation of histone gene transcription by nonhistone chromosomal phosphoproteins. Science. 1976 Oct 22;194(4263):428-31.

  • Stein JL, Thrall CL, Park WD, Mans RJ, Stein GS. Hybridization analysis of histone messenger RNA: association with polyribosomes during the cell cycle. Science. 1975 Aug 15;189(4202):557-8.