Spontaneous multifocal pyogenic granulomas.

Cutaneous pyogenic granulomas (PGs) are common, benign vascular tumors of uncertain pathogenesis; however, a growing body of literature suggests that the formation of PGs may be secondary to genetic alterations in both the Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. We present three cases of spontaneous multifocal PGs that first presented in infancy, were not associated with other vascular anomalies or discernable etiology, harbored somatic genetic variants in the Ras/Raf/MAPK pathway (NRAS n = 2, FGFR1 n = 1), were refractory to treatment with beta-blockers and mTOR inhibitors, and responded best to pulsed dye laser. We propose the term "spontaneous multifocal PGs" to describe this entity.

The Hsp70 co-chaperone Ydj1/HDJ2 regulates ribonucleotide reductase activity.

Hsp70 is a well-conserved molecular chaperone involved in the folding, stabilization, and eventual degradation of many "client" proteins. Hsp70 is regulated by a suite of co-chaperone molecules that assist in Hsp70-client interaction and stimulate the intrinsic ATPase activity of Hsp70. While previous studies have shown the anticancer target ribonucleotide reductase (RNR) is a client of Hsp70, the regulatory co-chaperones involved remain to be determined. To identify co-chaperone(s) involved in RNR activity, 28 yeast co-chaperone knockout mutants were screened for sensitivity to the RNR-perturbing agent Hydroxyurea. Ydj1, an important cytoplasmic Hsp70 co-chaperone was identified to be required for growth on HU. Ydj1 bound the RNR subunit Rnr2 and cells lacking Ydj1 showed a destabilized RNR complex. Suggesting broad conservation from yeast to human, HDJ2 binds R2B and regulates RNR stability in human cells. Perturbation of the Ssa1-Ydj1 interaction through mutation or Hsp70-HDJ2 via the small molecule 116-9e compromised RNR function, suggesting chaperone dependence of this novel role. Mammalian cells lacking HDJ2 were significantly more sensitive to RNR inhibiting drugs such as hydroxyurea, gemcitabine and triapine. Taken together, this work suggests a novel anticancer strategy-inhibition of RNR by targeting Hsp70 co-chaperone function.