Mohammed Shoyab

The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity

We have isolated the gene for a novel growth regulator, amphiregulin (AR), that is evolutionarily related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). AR is a bifunctional growth modulator: it interacts with the EGF/TGF-alpha receptor to promote the growth of normal epithelial cells and inhibits the growth of certain aggressive carcinoma cell lines. The 84-amino-acid mature protein is embedded within a 252-amino-acid transmembrane precursor, an organization similar to that of the TGF-alpha precursor. Human placenta and ovaries were found to express significant amounts of the 1.4-kilobase AR transcript, implicating AR in the regulation of normal cell growth. In addition, the AR gene was localized to chromosomal region 4q13-4q21, a common breakpoint for acute lymphoblastic leukemia.

Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways

Propagation of the undifferentiated pluripotential phenotype of embryonic stem (ES) cells is dependent on the cytokine differentiation inhibiting activity/leukemia inhibitory factor (DIA/LIF). The DIA/LIF receptor complex is a heterodimer of DIA/LIF receptor (DIA/LIF-R) and gp130. The latter is also a component of the interleukin-6 (IL-6) receptor complex. We report that a combination of IL-6 and soluble IL-6 receptor (sIL-6R), which can induce homodimerisation of gp130 and activation of signalling processes, sustains self-renewal of pluripotential ES cells. Our findings indicate that the IL-6/sIL-6R complex acts on ES cells through gp130 alone, bypassing DIA/LIF-R, and therefore implicate gp130 as the key component in the signalling pathway responsible for stem cell renewal.

The role of amphiregulin in breast cancer

SummaryAmphiregulin (AR) is an epidermal growth factor (EGF)-related peptide that operates exclusively through the EGF receptor and that can bind to heparin. AR also possesses nuclear localization sequences in the extended NH2-terminal region suggesting an additional intracellular site of action. AR mRNA and protein expression have been detected in primary human mammary epithelial cell strains, nontransformed human mammary epithelial cell lines, several human breast cancer cell lines, and primary human breast carcinomas. The frequency and levels of AR protein expression are generally higher in invasive breast carcinomas than in ductal carcinomasin situ or in normal, noninvolved mammary epithelium. In addition, AR can function as an autocrine and/or juxtacrine growth factor in human mammary epithelial cells that have been transformed by an activated c-Ha-ras proto-oncogene or by overexpression of c-erb B-2. AR expression is also enhanced by mammotrophic hormones such as estrogens and other growth factors such as EGF.

Chlorpromazine and related antipsychotic tricyclic compounds competitively inhibit the interaction between tumor-promoting phorbol esters and their specific receptors.

Various antipsychotic and antidepressant drugs have been tested for their effects on the binding of [3H] phorbol-dibutyrate (PDBu) to its specific receptor. Chlorpromazine and related antipsychotic tricyclic compounds competitively inhibit the interaction between tumor-promoting phorbol esters and their specific receptors. The relative potency of drugs in competing for [3H]PDBU to receptors is fluphenzine greater than flupenthioxal greater than 2-chloroimipramine greater than chlorpromazine greater than imipramine. The significance of these findings is discussed with special reference to the potential tumor-promoting activity of these drugs.

Enhancement by fluphenazine of dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats

Mammary tumor formation in female Sprague-Dawley rats was studied as a 2-stage protocol of initiation with 7,12 dimethylbenz[a]anthracene (DMBA) followed by repeated treatment with fluphenazine decanoate. No mammary tumors were found in the untreated control group or in the fluphenazine-treated groups. The repeated fluphenazine treatment was found to increase the number of mammary tumors in rats who had previously received DMBA and also to shorten the tumor latency period. The significance of these findings is discussed.