Heregulin β1 induces the down regulation and the ubiquitin-proteasome degradation pathway of p185HER2 oncoprotein

AbstractAnalysis of the fate of the p185HER2 oncoprotein following activation by heregulin β1 revealed the induction of the tyrosine-phosphorylation, down-modulation, and polyubiquitination of p185HER2. Receptor ubiquitination was suppressed in cells treated with heregulin β1 in the presence of sodium azide, an inhibitor of ATP-dependent reactions, or genistein, a tyrosine kinase protein inhibitor, indicating the requirement for kinase activity and ATP in p185HER2 polyubiquitination. Ubiquitinated p185HER2 was degradated by the 26S proteasome proteolytic pathway. Kinetics and inhibition experiments indicated that endocytosis of the receptor occurs downstream of the initiation of the degradation process

Protection against doxorubicin-induced alopecia in rats by liposome-entrapped monoclonal antibodies

Alopecia is a common side effect of several anti-cancer drugs, including doxorubicin. Based on our recent observation that a monoclonal antibody (MAD11) directed against this anthracycline inhibits the systemic toxic effect of the drug in mice, we investigated the possibility that MAD11 administered topically might protect against doxorubicin-induced alopecia. In 31 of 45 young rats treated intraperitoneally with doxorubicin, alopecia was completely prevented by topical treatment of the skin with liposome-incorporated anti-doxorubicin monoclonal antibody. This type of treatment might find relevance in preventing anthracycline-induced alopecia in cancer patients. Our findings also provide the first demonstration that liposome-entrapped monoclonal antibodies are capable of penetrating the stratum corneum of the skin without losing their function

Cooperative effects of Mycobacterium tuberculosis Ag38 gene trasduction and interleukin 12 in vaccination against spontaneous tumor development in proto-neu transgenic mice.

An approach to stimulating an immune response against tumors is to transduce tumor cells with bacterial genes, which represent a "danger signal" and can induce a wide immune response. Mycobacterium tuberculosis genes and their encoded proteins play a pivotal role in linking innate and cell-mediated adaptive immunity and represent ideal candidates as immune adjuvants for tumor vaccines. The efficacy of a cancer vaccine, obtained by transduction of a mammary tumor cell line with the M. tuberculosis Ag38 gene, was investigated in female mice transgenically expressing the rat HER-2/neu proto-oncogene. These mice spontaneously develop stochastic mammary tumors after a long latency period. The onset of spontaneous mammary tumors was significantly delayed in mice vaccinated with Ag38-transduced cells but not in mice vaccinated with nontransduced cells as compared with untreated mice. Protection from spontaneous tumor development was increased when mice were vaccinated with the mycobacterium gene-transduced vaccine plus a systemic administration of interleukin 12 (IL-12) at a low dose. Mice vaccinated with nontransduced cells plus IL-12 developed tumors, with only a slight delay in tumor appearance as compared with the control group. Lymphocytes obtained from lymph nodes of mice vaccinated with transduced cells secreted high levels of IFN-\u3b3. CD3 +CD8 + spleen cells derived from these mice responded to the tumor with IFN-\u3b3 production. These data indicate the efficacy of a short-term protocol of vaccinations exploiting the adjuvant potency of a M. tuberculosis gene and low doses of IL-12 in a model of stochastic development of mammary tumors. This adjuvant approach may represent a promising immunotherapeutic strategy for cancer immunization