Biomedical subjects
Publications and source records attributed to Laura A Lee.
The transition from oocyte to embryo is among the most enthralling events in developmental biology. Recent studies of this transition in the nematode Caenorhabditis elegans have revealed how conserved kinases administer the destruction of key oocyte meiotic regulators to create an embryo.
BACKGROUND: Previous studies on the efficacy of primary treatments for ductal carcinoma-in-situ (DCIS) have focused on local recurrence rates. Our objective was to detail the outcomes of local invasive recurrence, distant recurrence, and breast cancer mortality in patients previously treated for DCIS. METHODS: Clinical, pathologic, and outcome data were collected prospectively for 1236 patients with pure DCIS accrued from 1972 through 2005. RESULTS: There were 150 recurrences (87 DCIS and 63 invasive). Invasive local recurrence after mastectomy was rare (0.5% of patients) and after breast preservation was more frequent (12.0% of patients). The 12-year probabilities of breast cancer-specific mortality after mastectomy and after breast preservation were 0.8% and 1.0%, respectively. The 12-year breast cancer-specific mortality and distant disease probability for the 63 patients with invasive recurrences were 12% and 15%, respectively. CONCLUSIONS: Regardless of initial treatment, most patients with invasive local recurrence after treatment for DCIS can be treated and cured.
BACKGROUND: A previous study showed a 3% local recurrence risk at 8 years in ductal carcinoma in situ (DCIS) patients treated with excision alone with surgical margins of 10 mm or greater. This study updates those data. METHODS: A total of 272 DCIS patients treated conservatively with 10 mm or greater margins were reviewed in a prospective database. RESULTS: Among 212 excision-alone patients, there were 9 DCIS and 3 invasive recurrences. The 12-year probability of any local recurrence was 13.9%; of invasive recurrence it was 3.4%. Among 60 excision plus radiation patients, there was 1 local (invasive) recurrence (P = .06). The 12-year probability of local recurrence was 2.5%. CONCLUSIONS: Local recurrence in DCIS patients treated with excision alone with margins of 10 mm or greater compares favorably with local recurrence in DCIS patients with nontransected margins and treated with postoperative radiation. The risk of invasive recurrence among widely excised DCIS patients is extremely low.
Although traditional organism-based mutational analysis is powerful in identifying genes involved in specific biological processes, limitations include incomplete coverage and time required for gene identification. Biochemical screens using cell transfection or yeast two-hybrid methods are rapid, but they are limited by cDNA library quality. The recent establishment of "uni-gene sets" has made it feasible to biochemically screen an organism's entire genome. Radiolabeled protein pools prepared from the Drosophila Gene Collection were used in a Drosophila in vitro expression cloning ("DIVEC") screen for substrates of PAN GU kinase, which is crucial for S-M embryonic cell cycles. Ablation of one identified substrate, Mat89Bb, by RNAi produces a polyploid phenotype similar to that of pan gu mutants. Xenopus embryos injected with Mat89Bb morpholinos arrest with polyploid nuclei, and Mat89Bb RNAi in HeLa cells gives rise to multinucleated cells. Thus, Mat89Bb plays an evolutionarily conserved role as a crucial regulator of both cell cycle and development.
Early embryonic cell cycles in Drosophila consist of rapidly alternating S and M phases. Three genes, pan gu (png), plutonium (plu), and giant nuclei (gnu) coordinate these early S-M cycles by ensuring adequate Cyclin B protein levels. Mutations in any of these genes result in unregulated DNA replication and a lack of mitosis ("giant nuclei" phenotype). png encodes a serine/threonine protein kinase, and plu and gnu encode small, novel proteins. We show that PNG, PLU, and GNU constitute a novel protein kinase complex that specifically regulates S-M cell cycles. All three proteins are required for PNG kinase activity and are phosphorylated by PNG in vitro. Yeast two-hybrid screening revealed a direct interaction between PNG and PLU, and their co-expression is required for physical association and activation of PNG kinase. Artificial dimerization of PLU via fusion to either GST or FK506 binding protein (in the presence of dimerizing agent) abrogates the requirement for GNU to activate PNG kinase. We propose a model in which GNU normally regulates embryonic cell cycles by promoting transient dimerization of a core PNG/PLU complex, thereby stimulating PNG kinase activity.
An intriguing aspect of cell cycle regulation is how cell growth and division are coordinated with developmental signals to produce properly patterned organisms of the appropriate size. Using the foundation laid by a detailed understanding of the regulators that intrinsically control progression through the cell cycle, links between developmental signals and the cell cycle are being elucidated. Considerable progress has been made using Drosophila melanogaster, both in identifying new cell cycle regulators that respond to developmental cues and in defining the impact of extrinsic signals on homologs of mammalian oncogenes and tumor suppressors. In this review, we discuss each cell cycle phase, highlighting differences between archetypal and variant cell cycles employed for specific developmental strategies. We emphasize the interplay between developmental signals and cell cycle transitions. Developmental control of checkpoints, cell cycle exit, and cell growth are also addressed.