Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autocrine epidermal growth factor receptor activation by transforming growth factor alpha (TGF alpha) has been implicated in growth stimulation during epithelial neoplasia. Using keratinocytes isolated from mice with genetic defects in TGF alpha expression, we tested whether TGF alpha is required for transformation by the v-rasHa oncogene. Introduction of v-rasHa into primary epidermal cultures using a retroviral vector stimulated growth of both control (TGF alpha +/+, BALB/c) and TGF alpha-deficient (TGF alpha -/-, wa-1) keratinocytes. Moreover, v-rasHa elicited characteristic changes in marker expression (keratin 1 was suppressed; keratin 8 was induced), previously shown to be associated with epidermal growth factor (EGF) receptor activation, in both TGF alpha +/+ and TGF alpha -/- keratinocytes. v-rasHa markedly increased secreted (> 10-fold) and cell-associated (2-3-fold) TGF alpha levels in keratinocytes from TGF alpha +/+ and BALB/c mice, but not TGF alpha -/- or wa-1 mice. Based on Northern blot analysis, v-rasHa induced striking up-regulation of transcripts encoding the additional EGF family members amphiregulin, heparin-binding EGF-like growth factor, and betacellulin in cultured keratinocytes from all four mouse strains. Interestingly, in addition to the normal 4.5-kilobase TGF alpha transcript, wa-1 keratinocytes expressed two additional TGF alpha transcripts, 4.7 and 5.2 kilobases long. All three transcripts were up-regulated in response to v-rasHa, as well as exogenous TGF alpha or keratinocyte growth factor treatment, and were also detected in RNA isolated from wa-1 brain and skin. In vivo, v-rasHa keratinocytes from control as well as TGF alpha-deficient mice produced squamous tumors when grafted onto nude mice, and these lesions expressed high levels of amphiregulin, heparin-binding EGF-like growth factor, and betacellulin mRNA, regardless of their TGF alpha status. These findings indicate that TGF alpha is not essential for epidermal neoplasia induced by the v-rasHa oncogene and suggest that another EGF family member(s) may contribute to autocrine growth stimulation of ras-transformed keratinocytes.
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PMID:Autocrine transforming growth factor alpha is dispensible for v-rasHa-induced epidermal neoplasia: potential involvement of alternate epidermal growth factor receptor ligands. 772 56

Transforming growth factor beta (TGF-beta) inhibits proliferation of keratinocytes cultured from normal anogenital epithelia; however, human papillomavirus (HPV)-immortalized cell lines often exhibit increased resistance. Present results demonstrate that TGF-beta 1 (1-10 pM) stimulates growth of multiple HPV-immortalized cell lines when cultures are maintained under conditions promoting squamous differentiation (MCDB153-LB medium with 1.0 mM calcium and without epidermal growth factor and bovine pituitary extract). Growth stimulation by TGF-beta 1 was not due to altered expression of type I or II receptors, but was increased after extended passage of cells in culture. Differentiation of immortal keratinocytes resulted in induction of RNAs encoding two markers of squamous differentiation, involucrin and keratin 1, and decreased expression of RNAs for the epidermal growth factor (EGF) receptor and two ligands, amphiregulin and TGF-alpha. Growth stimulation by TGF-beta 1 occurred indirectly via establishment of an autocrine loop. TGF-beta 1 increased expression of RNAs encoding the EGF-R and amphiregulin, and also increased numbers of cell-surface EGF-Rs without altering their affinity. In contrast, TGF-beta 1 inhibited autonomous growth and transcription of amphiregulin RNA in normal keratinocytes. Growth stimulation by TGF-beta 1 could be blocked by a monoclonal antibody that competes for binding to the EGF-R or by a mixture of monoclonal antibodies that neutralize amphiregulin activity, confirming the importance of this autocrine pathway. Thus, partial abrogation of the growth inhibitory response to TGF-beta 1 sensitizes HPV-immortalized keratinocytes to a growth stimulatory signal mediated by an EGF-R-dependent pathway involving autocrine stimulation by amphiregulin.
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PMID:Transforming growth factor beta 1 supports autonomous growth of human papillomavirus-immortalized cervical keratinocytes under conditions promoting squamous differentiation. 878 Aug 94

To directly compare the expression patterns of different proteins known to be altered during mouse skin carcinogenesis, serial sections of normal and hyperplastic skin and tumors from various stages of 7,12-dimethylbenz[a]anthracene-initiated, 12-O-tetradecanoylphorbol-13-acetate-promoted female SENCAR mice were examined by immunohistochemistry. In untreated, normal mouse skin, keratin 1 (K1) and transforming growth factor-beta1 (TGFbeta1) were strongly expressed in the suprabasal layers, whereas integrin alpha6beta4 was expressed only in basal cells and only moderate staining for transforming growth factor-alpha (TGFalpha) was seen. In hyperplastic skin, TGFalpha expression became stronger, whereas expression of another epidermal growth factor (EGF) receptor ligand, heparin-binding EGF-like growth factor (HB-EGF), was strongly induced in all epidermal layers from no expression in normal skin. Likewise, the gap-junctional protein connexin 26 (Cx26) became highly expressed in the differentiated granular layers of hyperplastic skin relative to undetectable expression in normal skin. Expression of cyclin D1 in the proliferative cell compartment was seen in all benign and malignant tumors but not in hyperplastic skin. Beginning with very early papillomas (after 10 wk of promotion), expression of alpha6beta4 in suprabasal cells and small, focal staining for keratin 13 (K13) were seen in some tumors. Later (after 20-30 wk), focal areas of gamma-glutamyl transpeptidase (GGT) activity appeared in a few papillomas, whereas TGFbeta1 expression began to decrease. Cx26 and TGFalpha staining became patchier in some late-stage papillomas (30-40 wk), whereas suprabasal alpha6beta4, K13, and GGT expression progressively increased and K1 expression decreased. Finally, in squamous cell carcinomas (SCCs), there was an almost complete loss of K1 and a further decline in TGFalpha, HB-EGF, TGFbeta1, and Cx26 expression. On the other hand, almost all SCCs showed suprabasal staining for alpha6beta4 and widespread cyclin D1 and K13 expression, whereas only about half showed positive focal staining for GGT activity.
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PMID:Changes in protein expression during multistage mouse skin carcinogenesis. 932 43

Keratin intermediate filaments are heteropolymers composed of type I and type II keratins. Ultraviolet B (UVB) irradiation induces keratin expression by keratinocytes. Using SV40-transformed human keratinocytes (SVHK), we investigated the effect of UVB irradiation on keratin expression. UVB irradiation (10 mJ/cm(2)) increased keratin 5 and keratin 14 mRNAs and proteins without affecting cell viability. Upregulation of keratin 5 and keratin 14 was dependent on the dose of radiation: the effect was observed at 5 mJ/cm(2) and the maximal effect was observed at 10 mJ/cm(2). Higher UVB doses (more than 10 mJ/cm(2)) were cytotoxic. Expression of keratin 1 and keratin 10 was marginal in SVHK and was not affected at either the mRNA or protein level by UVB. The stimulatory effects on keratin 5 and keratin 14 expression were also observed in cultured normal human keratinocytes (NHK) and HaCaT keratinocytes. The tyrosine kinase inhibitor, genistein, and the epidermal growth factor (EGF) receptor inhibitor, AG1429, significantly suppressed the increase in expression of keratin 5 and keratin 14 by SVHK. In contrast, the suppressive effect was not observed with the protein kinase C inhibitor, H-7. Furthermore, pretreatment with neutralizing anti-EGF receptor antibody also suppressed UVB-induced keratin 5 and keratin 14 expression by SVHK, NHK and HaCaT cells. UVB irradiation did not affect the steady-state expression of TGF-alpha by SVHK. Immunoprecipitation and immunohistochemical studies revealed that UVB irradiation induced EGF receptor activation in the absence of EGF and TGF-alpha. These results indicate that UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK.
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PMID:Ultraviolet B irradiation increases keratin 5 and keratin 14 expression through epidermal growth factor receptor of SV40-transformed human keratinocytes. 1187 47