Subcellular and Cell-Cycle Expression Profiles of CDK-Inhibitors in Normal Differentiating Myeloid Cells

Yaroslavskiy, Beatrice B.; Watkins, Simon C.; Donnenberg, A. D.; Patton, Timothy; Steinman, Richard A.

doi:10.1182/blood.v93.9.2907

Cited by 67 publications

(27 citation statements)

References 22 publications

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“…77 Therefore, p21 plays a role in at least some cell types in the transition out of the cell cycle and the maintenance of cells in G 0 . However, in hematopoiesis, the expression levels of p21 is not as high as one might expect in CD34 + cells, 78,79 and p21-null mice do not exhibit an altered hematologic profile. 75,76 Nevertheless, in a subsequent analysis, Cheng et al did find that p21 is indeed highly expressed in the quiescent stem cell-like fraction of BM cells.…”

Section: Roles Of P21 and P27 In Quiescence Of Hscs And Progenitor Cellsmentioning

confidence: 82%

“…In the hematopoietic system, the expression of p27 is observed in more mature progenitors than p21. 78,79 The p27 -/mice have a larger body and hyperplasia of most organs including the hematopoietic organs. [81][82][83] In striking contrast to p21 -/mice, the number, cell cycling and self-renewal of HSCs were normal in p27-null mice, while these mice had an increase in hematopoietic progenitor cells.…”

Section: Roles Of P21 and P27 In Quiescence Of Hscs And Progenitor Cellsmentioning

confidence: 99%

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Cell Cycle Regulation in Hematopoietic Stem/Progenitor Cells

Ezoe¹,

Matsumura²,

Satoh³

et al. 2004

Cell Cycle

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Hematopoietic stem cells (HSCs) are characterized by pluripotentiality and a capacity for self-renewal. In order to both maintain a supply of mature blood cells and not to exhaust HSCs throughout the lifespan of the organism, most HSCs remain quiescent and only a limited number enter the cell cycle. In HSCs, the cell cycle is crucially regulated by external factors such as cytokines and interactions with stromal cells and the extracellular matrix (ECM) in the bone marrow (BM) microenvironment. In addition, intrinsic transcription factors expressed in HSCs, including c-Myb, GATA-2, HOX family proteins, and Bmi-1, also control their growth through their effect on gene transcription. In terms of the particular roles in regulation of the cell-cycle, p21 WAF1 (p21) and p27 KIP1 (p27) were shown to maintain the quiescence of HSCs and of progenitor cells, respectively, thereby governing their available pool sizes. Also, p16 INK4A (p16) and p15 INK4B (p15) are thought to act as tumor suppressors, since their inactivation and/or deletion are observable in various types of hematologic malignancies. These results make evident that appropriate cell cycle control, particularly at the early stage of stem/progenitor cells, is required for maintaining normal hematopoiesis. © L a n d e s B i o s c i e n c e 2 0 0 4. N o t f o r d i s t r i b u t i o n .

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Section: Roles Of P21 and P27 In Quiescence Of Hscs And Progenitor Cellsmentioning

confidence: 82%

Section: Roles Of P21 and P27 In Quiescence Of Hscs And Progenitor Cellsmentioning

confidence: 99%

Cell Cycle Regulation in Hematopoietic Stem/Progenitor Cells

Ezoe¹,

Matsumura²,

Satoh³

et al. 2004

Cell Cycle

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“…Moreover, PCNA could use its cognate partners possessing an NLS as cargo proteins for active import. This is the case in p21 Cip1/Waf1 , which has its own NLS and whose expression is down-regulated during granulocytic differentiation (11). As no mechanisms governing the active export of PCNA have been described so far, we investigated whether PCNA contains a functional CRM1 (chromosomal region maintenance 1)-dependent nuclear export signal (NES).…”

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confidence: 99%

Nuclear-to-cytoplasmic Relocalization of the Proliferating Cell Nuclear Antigen (PCNA) during Differentiation Involves a Chromosome Region Maintenance 1 (CRM1)-dependent Export and Is a Prerequisite for PCNA Antiapoptotic Activity in Mature Neutrophils

Bouayad

Pederzoli-Ribeil

Mocek

et al. 2012

Journal of Biological Chemistry

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Neutrophils are deprived of proliferative capacity and have a tightly controlled lifespan to avoid their persistence at the site of injury. We have recently described that the proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repair of proliferating cells, is a key regulator of neutrophil survival. In neutrophils, PCNA was localized exclusively in the cytoplasm due to its nuclear-to-cytoplasmic relocalization during granulocytic differentiation. We showed here that leptomycin B, an inhibitor of the chromosome region maintenance 1 (CRM1) exportin, inhibited PCNA relocalization during granulocytic differentiation of HL-60 and NB4 promyelocytic cell lines and of human CD34(+) primary cells. Using enhanced green fluorescent protein fusion constructs, we have demonstrated that PCNA relocalization involved a nuclear export signal (NES) located from Ile-11 to Ile-23 in the PCNA sequence. However, this NES, located at the inner face of the PCNA trimer, was not functional in wild-type PCNA, but instead, was fully active and leptomycin B-sensitive in the monomeric PCNAY114A mutant. To test whether a defect in PCNA cytoplasmic relocalization would affect its antiapoptotic activity in mature neutrophils, a chimeric PCNA fused with the SV40 nuclear localization sequence (NLS) was generated to preclude its cytoplasmic localization. As expected, neutrophil-differentiated PLB985 cells expressing ectopic SV40NLS-PCNA had an increased nuclear PCNA as compared with cells expressing wild-type PCNA. Accordingly, the nuclear PCNA mutant did not show any antiapoptotic activity as compared with wild-type PCNA. Nuclear-to-cytoplasmic relocalization that occurred during myeloid differentiation is essential for PCNA antiapoptotic activity in mature neutrophils and is dependent on the newly identified monomerization-dependent PCNA NES.

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“…Confocal microscopy for p27 was performed using a Leica (TCS-NT) confocal microscope (Leica, Deerfield, IL) as previously described (13). In brief, 1 million cells were washed in phosphate-buffered saline (PBS) containing 2% FBS and 0.5% azide (washing buffer), fixed with 1% paraformaldehyde, suspended in 75% cold ethanol and stored at Ϫ20ЊC.…”

Section: Confocal Microscopymentioning

confidence: 99%

“…Several studies indicate that, in addition to total p27 levels, the subcellular localization of p27 may modulate p27 function. Whereas, p27 is nuclear in quiescent myeloid precursor cells, it accumulates in the cytoplasm of these cells following cytokine activation (13). Cytoplasmic expression of p27 also has been reported in esophageal, ovarian (14), and colorectal cancers (15,16).…”

Section: Introductionmentioning

confidence: 99%