Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7 α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

The BRCA1 tumor suppressor has been implicated in many cellular pathways, but the mechanisms by which it suppresses tumor formation are not fully understood. In vivo BRCA1 forms a heterodimeric complex with the related BARD1 protein, and its enzymatic activity as a ubiquitin ligase is largely dependent upon its interaction with BARD1. To explore the genetic relationship between BRCA1 and BARD1, we have examined the phenotype of Bard1-null mice. These mice become developmentally retarded and die between embryonic day 7.5 (E7.5) and E8.5. Embryonic lethality results from a severe impairment of cell proliferation that is not accompanied by increased apoptosis. In the absence of p53, the developmental defects associated with Bard1 deficiency are partly ameliorated, and the lethality of Bard1; p53-nullizygous mice is delayed until E9.5. This result, together with the increased chromosomal aneuploidy of Bard1 mutant cells, indicates a role for Bard1 in maintaining genomic stability. The striking similarities between the phenotypes of Bard1-null, Brca1-null, and double Bard1; Brca1-null mice provide strong genetic evidence that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer.Germ line mutations of the BRCA1 tumor suppressor gene are responsible for many cases of hereditary breast and ovarian carcinomas (34), and its protein product has been implicated in a broad spectrum of cellular processes that includes transcriptional regulation, chromatin remodeling, DNA repair, and cell cycle checkpoint control (for recent reviews, see references 2, 25, 35, 42, and 49). The major isoform of Brca1 has two recognizable amino acid motifs: a RING domain at the N terminus and two tandem copies of the BRCT domain at the C terminus (29, 34). In some patients, the predisposing BRCA1 lesion can be traced to missense mutations in the RING domain (8, 44), indicating that proper folding of this motif is essential for BRCA1-mediated tumor suppression. Many RING proteins are now known to function as ubiquitin E3 ligases, a family of enzymes that catalyze the final step in protein ubiquitination (22,24). Recent studies have shown that the N-terminal RING sequence of BRCA1 can also catalyze the formation of polyubiquitin chains in vitro and that this activity is abolished by tumor-associated missense mutations (7,17,32,39).The in vivo functions of BRCA1 have been explored using genetically modified mice bearing either null Brca1 alleles, which are completely devoid of Brca1 activity and/or expression, or hypomorphic alleles that presumably retain some aspects of normal Brca1 activity (reviewed in references 4 and 19). Mice that are heterozygous for Brca1 mutations, whether null or hypomorphic, develop normally, but unlike human carriers of BRCA1 mutations, they are not predisposed to mammary carcinogenesis. On the other hand, mice that are homozygous for null Brca1 alleles die around the time of gastrulation, typically between days 6.5 and 7.5 of embryogenesis (15,31,33). Brca1-null embryos are not char...

Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT), originally described as distinct entities, share overlapping clinical findings. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. FC, however, is characterized by cylindromas and MFT by trichoepitheliomas as the only tumor type. These disorders have recently been associated with mutations in the CYLD gene. In this report, we describe three families with BSS, one with FC, and two with MFT phenotypes associated with novel and recurrent mutations in CYLD. We provide evidence that these disorders represent phenotypic variation of a single entity and lack genotype-phenotype correlation.